1,3-Diheterocyclic metalloprotease inhibitors

ABSTRACT

The invention provides compounds of formula  
                 
 
     as described in the claims, or an optical isomer, diastereomer or enantiomer thereof, or a pharmaceutically-acceptable salt, or biohydrolyzable amide, ester, or imide thereof are useful as inhibitors of metalloproteases.  
     Also disclosed are pharmaceutical compositions and methods of treating diseases, disorders and conditions characterized by metalloprotease activity using these compounds or the pharmaceutical compositions containing them.

CROSS REFERENCE

[0001] This application claims priority under Title 35, United StatesCode 119(e) from Provisional Application Serial No. 60/024,830, filedAug. 28, 1996.

TECHNICAL FIELD

[0002] This invention is directed to compounds which are useful intreating diseases, disorders and conditions associated with unwantedmetalloprotease activity.

BACKGROUND

[0003] A number of structurally related metalloproteases [MPs] effectthe breakdown of structural proteins. These metalloproteases often acton the intercellular matrix, and thus are involved in tissue breakdownand remodeling. Such proteins are referred to as metalloproteases orMPs. There are several different families of MPs, classified by sequencehomology. Several families of known MPs, as well as examples thereof,are disclosed in the art.

[0004] These MPs include Matrix-Metallo Proteases [MMPs], zincmetalloproteases, many of the membrane bound metalloproteases, TNFconverting enzymes, angiotensin-converting enzymes (ACEs), disintegrins,including ADAMs (See Wolfsberg et al, 131 J. Cell Bio. 275-78 October,1995), and the enkephalinases. Examples of MPs include human skinfibroblast collagenase, human skin fibroblast gelatinase, human sputumcollagenase, aggrecanse and gelatinase, and human stromelysin.Collagenase, stromelysin, aggrecanase and related enzymes are thought tobe important in mediating the symptomatology of a number of diseases.

[0005] Potential therapeutic indications of MP inhibitors have beendiscussed in the literature. See for example, U.S. Pat. No. 5,506,242(Ciba Geigy Corp.); U.S. Pat. No. 5,403,952 (Merck & Co.); PCT publishedapplication WO 96/06074 (British Bio Tech Ltd); PCT Publication WO96/00214 (Ciba Geigy); WO 95/35275 (British Bio Tech Ltd); WO 95/35276(British Bio Tech Ltd); WO 95/33731 (Hoffman-LaRoche); WO 95/33709(Hoffman-LaRoche). WO 95/32944 (British Bio Tech Ltd); WO 95/26989(Merck), WO 9529892 (DuPont Merck); WO 95/24921 (Inst. Opthamology); WO95/23790 (SmithKline Beecham), WO 95/22966 (Sanofi Winthrop); WO95/19965 (Glycomed); WO 95 19956 (British Bio Tech Ltd); WO 95/19957(British Bio Tech Ltd); WO 95/19961 (British Bio Tech Ltd) WO 95/13289(Chiroscience Ltd.); WO 95/12603 (Syntex); WO 95/09633 (Florida StateUniv); WO 95/09620 (Florida State Univ.); WO 95/04033 (Celltech); WO94/25434 (Celltech); WO 94/25435 (Celltech); WO 93/14112 (Merck); WO9410019 (Glaxo); WO 93/21942 (British Bio Tech Ltd); WO 92/22523 (Res.Corp. Tech. Inc.), WO 94/10990 (British Bio Tech Ltd); WO 93/09090(Yamanouchi); and British patents GB 2282598 (Merck) and GB 2268934(British Bio Tech Ltd); Published European Patent Applications EP95/684240 (Hoffman LaRoche); EP 574758 (Hoffman LaRoche); EP 575844(Hoffman LaRoche); Published Japanese applications; JP 08053403(Fujusowa Pharm. Co. Ltd.); JP 7304770 (Kanebo Ltd.); and Bird et al J.Med Chem vol. 37, pp. 158-69 (1994). Examples of potential therapeuticuses of MP inhibitors include rheumatoid *. arthritis (Mullins, D. E.,et al., Biochim. Biophys. Acta. (1983) 695:117-214); osteoarthritis(Henderson. B., et al., Drugs of the Future (1990) 15:495-508); themetastasis of tumor cells (ibid, Broadhurst, M. J., et al., EuropeanPatent Application 276,436 (published 1987), Reich, R., et al., 48Cancer Res. 3307-3312 (1988); and various or ulcerative conditions oftissue. For example, ulcerative conditions can result in the cornea asthe result of alkali burns or as a result of infection by Pseudomonasaeruginosa, Acanthamoeba. Herpes simplex and vaccinia viruses.

[0006] Other examples of conditions characterized by undesiredmetalloprotease activity include periodontal disease, epidermolysisbullosa, fever, inflammation and scleritis (Cf. DeCicco et al, WO 9529892 published Nov. 9, 1995).

[0007] In view of the involvement of such metalloproteases in a numberof disease conditions, attempts have been made to prepare inhibitors tothese enzymes. A number of such inhibitors are disclosed in theliterature. Examples include U.S. Pat. No. 5,183,900, issued Feb. 2,1993 to Galardy; U.S. Pat. No. 4,996,358, issued Feb. 26, 1991 to Handa,et al.; U.S. Pat. No. 4,771,038, issued Sep. 13, 1988 to Wolanin, etal.; U.S. Pat. No. 4,743,587, issued May 10, 1988 to Dickens, et al.,European Patent Publication Number 575,844, published Dec. 29, 1993 byBroadhurst, et al.; International Patent Publication No. WO 93/09090,published May 13, 1993 by Isomura, et al.; World Patent Publication92/17460, published Oct. 15, 1992 by Markwell et al.; and EuropeanPatent Publication Number 498,665, published Aug. 12, 1992 by Beckett,et al.

[0008] Metalloprotease inhibitors are useful in treating diseasescaused, at least in part, by breakdown of structural proteins. Though avariety of inhibitors have been prepared, there is a continuing need forpotent matrix metalloprotease inhibitors useful in treating suchdiseases. Applicants have found that, surprisingly, the compounds of thepresent invention are potent metalloprotease inhibitors.

OBJECTS OF THE INVENTION

[0009] Thus it is an object of the present invention to providecompounds useful for the treatment of conditions and diseases which arecharacterized by unwanted MP activity.

[0010] It is also an object of the invention to provide potentinhibitors of metalloproteases.

[0011] It is a further object of the invention to provide pharmaceuticalcompositions comprising such inhibitors.

[0012] It is also an object of the invention to provide a method oftreatment for metalloprotease related maladies. SUMMARY OF THE INVENTION

[0013] The invention provides compounds which are useful as inhibitorsof metalloproteases, and which are effective in treating conditionscharacterized by excess activity of these enzymes. In particular, thepresent invention relates to a compound having a structure according toFormula (I)

[0014] wherein

[0015] R₁ is H;

[0016] R₂ is hydrogen, alkyl, or acyl;

[0017] Ar is COR₃ or SO₂R₄; and

[0018] R₃ is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl,heteroalkyl, amino, alkylamino, dialkylamino, arylarmino andalkylarylamino;

[0019] R₄ is alkyl, heteroalkyl, aryl, or heteroaryl, substituted orunsubstituted;

[0020] X is O, S, SO, SO₂, or NR₅, wherein R₅ is independently chosenfrom hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO₂R₆, COR₇, CSR₈,PO(R₉)₂ or may optionally form a ring with Y or W; and

[0021] R₆ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino;

[0022] R₇ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl,heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino andalkylarylamino;

[0023] R₈ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino;

[0024] R₉ is alkyl, aryl, heteroaryl, heteroalkyl;

[0025] W is hydrogen or one or more lower alkyl moieties, or aheterocycle, or is an alkylene, arylene or heteroarylene bridge betweentwo adjacent or nonadjacent carbons (thus forming a fused ring);

[0026] Y is independently one or more of hydrogen, hydroxy, SR₁₀, SOR₄,SO₂R₄, alkoxy, amino, wherein amino is of formula NR₁₁,R₁₂, wherein R₁₁and R₁₂ are independently chosen from hydrogen, alkyl, heteroalkyl,heteroaryl, aryl, SO₂R₆, COR₇, CSR₈, PO(R₉)₂; and

[0027] R₁₀ is hydrogen, alkyl, aryl, heteroaryl;

[0028] Z is nil, a spiro moiety or an oxo group substituted on theheterocyclic ring;

[0029] n is 1-4.

[0030] This structure also includes an optical isomer, diastereomer orenantiomer for Formula (I), or a pharmaceutically-acceptable salt, orbiohydrolyzable amide, ester, or imide thereof.

[0031] These compounds have the ability to inhibit at least onemammalian metalloprotease. Accordingly, in other aspects, the inventionis directed to pharmaceutical compositions containing the compounds ofFormula (I), and to methods of treating diseases characterized byunwanted metalloprotease activity using these compounds or thepharmaceutical compositions containing them.

[0032] Metalloproteases which are active at a particularly undesiredlocation (e.g., an organ or certain types of cells) can be targeted byconjugating the compounds of the invention to a targeting ligandspecific for a marker at that location such as an antibody or fragmentthereof or a receptor ligand. Conjugation methods are known in the art.

[0033] The invention is also directed to various other processes whichtake advantage of the unique properties of these compounds. Thus, inanother aspect, the invention is directed to the compounds of Formula(I) conjugated to solid supports. These conjugates can be used asaffinity reagents for the purification of a desired metalloprotease.

[0034] In another aspect, the invention is directed to the compounds ofFormula (I) conjugated to label. As the compounds of the invention bindto at least one metalloprotease, the label can be used to detect thepresence of relatively high levels of metalloprotease, preferably amatrix metalloprotease in vivo or in vitro cell culture.

[0035] In addition, the compounds of Formula (I) can be conjugated tocarriers which permit the use of these compounds in immunizationprotocols to prepare antibodies specifically immunoreactive with thecompounds of the invention. Typical conjugation methods are known in theart. These antibodies are then useful both in therapy and in monitoringthe dosage of the inhibitors.

DETAILED DESCRIPTION

[0036] The compounds of the present invention are inhibitors ofmammalian metalloproteases, preferably a matrix metalloproteases.Preferably, the compounds are those of Formula (I) or apharmaceutically-acceptable salt, or biohydrolyzable amide, ester, orimide thereof.

[0037] Throughout this disclosure, publications and patents are referredto in an effort to fully describe the state of the art. All referencescited herein are hereby incorporated by reference.

[0038] Definitions and Usage of Terms:

[0039] The following is a list of definitions for terms used herein.

[0040] “Acyl” or “carbonyl” is described as a radical which could beformed by removal of the hydroxy from a carboxylic acid (i.e. R—C(═O)—).Preferred acyl groups include (for example) acetyl, formyl, andpropionyl.

[0041] “Acyloxy” is an oxy radical having an acyl substituent (i.e.,—O-acyl); for example, —O—C(═O)-alkyl.

[0042] “Alkoxyacyl” is an acyl radical (—C(═O)—) having an alkoxysubstituent (i.e., —O—R), for example, —C(═O)—O-alkyl. This radical canbe referred to as an ester.

[0043] “Acylamino” is an amino radical having an acyl substituent (i.e.,—N-acyl); for example, —NH—C(═O)-alkyl.

[0044] “Alkenyl” is an unsubstituted or substituted hydrocarbon chainradical having 2 to 15 carbon atoms; preferably from 2 to 10 carbonatoms; more preferably from 2 to 8: except where indicated. Alkenylsubstituents have at least one olefinic double bond (including, forexample, vinyl, allyl and butenyl).

[0045] “Alkynyl” is an unsubstituted or substituted hydrocarbon chainradical having 2 to 15 carbon atoms; preferably from 2 to 10 carbonatoms; more preferably from 2 to 8; except where indicated. The chainhas at least one carbon-carbon triple bond.

[0046] “Alkoxy” is an oxygen radical having a hydrocarbon chainsubstituent, where the hydrocarbon chain is an alkyl or alkenyl (i.e.,—O-alkyl or —O-alkenyl). Preferred alkoxy groups include (for example)methoxy, ethoxy, propoxy and allyloxy.

[0047] “Alkoxyalkyl” is an unsubstituted or substituted alkyl moietysubstituted with an alkoxy moiety (i.e., -alkyl-O-alkyl). Preferred iswhere the alkyl has 1 to 6 carbon atoms (more preferably 1 to 3 carbonatoms), and the alkyoxy has 1 to 6 carbon atoms (more preferably 1 to 3carbon atoms).

[0048] “Alkyl” is an unsubstituted or substituted saturated hydrocarbonchain radical having 1 to 15 carbon atoms; preferably from 1 to 10carbon atoms; more preferably 1 to 4: except where indicated. Preferredalkyl groups include (for example) substituted or unsubstituted methyl,ethyl, propyl, isopropyl, and butyl.

[0049] As referred to herein, “spiro cycle” or “spiro cyclic” refers toa cyclic moiety sharing a carbon on another ring. Such cyclic moiety maybe carbocyclic or heterocyclic in nature. Preferred heteroatoms includedin the backbone of the heterocyclic spirocycle include oxygen, nitrogenand sulfur. The spiro cycles may be unsubstituted or substituted.Preferred substituents include oxo, hydroxy, alkyl, cycloalkyl,arylalkyl, alkoxy, amino, heteroalkyl, aryloxy, fused rings (e.g.,benzothiole, cycloalkyl, heterocycloalkyl, benzimidizoles,pyridylthiole, etc., which may also be substituted) and the like. Inaddition, the heteroatom of the heterocycle may be substituted ifvalence allows. Preferred spirocyclic ring sizes include 3-7 memberedrings.

[0050] Alkylene refers to an alkyl, alkenyl or alkynyl which isdiradical, rather than a radical. “Hetero alkylene” is likewise definedas a (diradical) alkylene having a heteroatom in its chain.

[0051] “Alkylamino” is an amino radical having one (secondary amine) ortwo (tertiary amine) alkyl substituents (i.e., —N-alkyl). For example,methylamino (—NHCH₃), dimethylamino (—N(CH₃)₂), methylethylamino(—N(CH₃)CH₂CH₃).

[0052] “Aminoacyl” is acyl radical having an amino substituent (i.e.,—C(═O)—N); for example, —C(═O)—NH—. The amino group of the aminoacylmoiety may be unsubstituted (i.e., primary amine) or may be substitutedwith one (secondary amine) or two (i.e., tertiary amine) alkyl groups.

[0053] “Aryl” is an aromatic carbocyclic rino radical. Preferred arylgroups include (for example) phenyl, tolyl, xylyl, cumenyl, naphthyl,biphenyl and fluorenyl. Such groups may be substituted or unsubstituted.

[0054] “Arylalkyl” is an alkyl radical substituted with an aryl group.Preferred arylalkyl groups include benzyl, phenylethyl, andphenylpropyl. Such groups may be substituted or unsubstituted.“Arylalkylamino” is an amine radical substituted with an arylalkyl group(e.g., —NH-benzyl). Such groups may be substituted or unsubstituted.

[0055] “Arylamino” is an amine radical substituted with an aryl group(i.e., —NH-aryl). Such groups may be substituted or unsubstituted.

[0056] “Aryloxy” is an oxygen radical having an aryl substituent (i.e.,—O-aryl). Such groups may be substituted or unsubstituted.

[0057] “Carbocyclic ring” is an unsubstituted or substituted, saturated,unsaturated or aromatic, hydrocarbon ring radical. Carbocyclic rings aremonocyclic or are fused, bridged or spiro polycyclic ring systems.Monocyclic carbocyclic rings generally contain 4 to 9 atoms, preferably4 to 7 atoms. Polycyclic carbocyclic rings contain 7 to 17 atoms,preferably from 7 to 12 atoms. Preferred polycyclic systems comprise 4-,5-, 6- or 7-membered rings fused to 5-, 6-, or 7-membered rings.

[0058] “Carbocycle-alkyl” is an unsubstituted or substituted alkylradical substituted with a carbocyclic ring. Unless otherwise specified,the carbocyclic ring is preferably an aryl or cycloalkyl; morepreferably an aryl. Preferred carbocycle-alkyl groups include benzyl,phenylethyl and phenylpropyl.

[0059] “Carbocycle-heteroalkyl” is an unsubstituted or substitutedheteroalkyl radical substituted with a carbocyclic ring. Unlessotherwise specified, the carbocyclic ring is preferably an aryl orcycloalkyl; more preferably an aryl. The heteroalkyl is preferably2-oxa-propyl, 2-oxa-ethyl, 2-thia-propyl, or 2-thia-ethyl.

[0060] “Carboxyalkyl” is an unsubstituted or substituted alkyl radicalsubstituted with a carboxy (—C(═O)OH) moiety. For example, —CH₂—C(═O)OH.

[0061] “Cycloalkyl” is a saturated carbocyclic ring radical. Preferredcycloalkyl groups include (for example) cyclopropyl, cyclobutyl andcyclohexyl.

[0062] “Cycloheteroalkyl” is a saturated heterocyclic ring. Preferredcycloheteroalkyl groups include (for example) morpholinyl, piperadinyl,piperazinyl, tetrahydrofuryl and hydantoinyl.

[0063] “Fused rings” are rings that are superimposed together such thatthey share two ring atoms. A given ring may be fused to more than oneother ring. Fused rings are contemplated in heteroaryl, aryl andheterocycle radicals or the like.

[0064] “Heterocycle-alkyl” is an alkyl radical substituted with aheterocyclic ring. The heterocyclic ring is preferably a heteroaryl orcycloheteroalkyl; more preferably a heteroaryl. Preferred heterocyclealkyl include C₁-C₄ alkyl having preferred heteroaryl appended to them.More preferred is, for example pyridyl alkyl, and the like.

[0065] “Heterocycle-heteroalkyl” is an unsubstituted or substitutedheteroalkyl radical substituted with a heterocyclic ring. Theheterocyclic ring is preferably an aryl or cycloheteroalkyl; morepreferably an aryl.

[0066] “Heteroatom” is a nitrogen, sulfur or oxygen atom. Groupscontaining one or more heteroatoms may contain different heteroatoms.

[0067] “Heteroalkenyl” is an unsubstituted or substituted unsaturatedchain radical having 3 to 8 members comprising carbon atoms and one ortwo heteroatoms. The chain has at least one carbon-carbon double bond.

[0068] “Heteroalkyl” is an unsubstituted or substituted saturated chainradical having 2 to 8 members comprising carbon atoms and one or twoheteroatoms.

[0069] “Heterocyclic ring” is an unsubstituted or substituted,saturated, unsaturated or aromatic ring radical comprised of carbonatoms and one or more heteroatoms in the ring. Heterocyclic rings aremonocyclic or are fused, bridged or spiro polycyclic ring systems.Monocyclic heterocyclic rings contain 3 to 9 atoms, preferably 4 to 7atoms. Polycyclic rings contain 7 to 17 atoms, preferably from 7 to 13atoms.

[0070] “Heteroaryl” is an aromatic heterocyclic ring, either monocyclicor bicyclic radical. Preferred heteroaryl groups include (for example)thienyl, furyl, pyrrolyl, pyridinyl, pyrazinyl, thiazolyl, pyrimidinyl,quinolinyl, and tetrazolyl, benzo thiazolyl, benzofuryl, indolyl and thelike. Such groups may be substituted or unsubstituted.

[0071] “Halo”, “halogen”, or “halide” is a chloro, bromo, fluoro or iodoatom radical. Bromo, chloro and fluoro are preferred halides.

[0072] Also, as referred to herein, a “lower” hydrocarbon moiety (e.g.,“lower” alkyl) is a hydrocarbon chain comprised of 1 to 6, preferablyfrom 1 to 4, carbon atoms.

[0073] A “pharmaceutically-acceptable salt” is a cationic salt formed atany acidic (e.g., carboxyl) group, or an anionic salt formed at anybasic (e.g., amino) group. Many such salts are known in the art, asdescribed in World Patent Publication 87/05297, Johnston et al.,published Sep. 11, 1987 (incorporated by reference herein). Preferredcationic salts include the alkali metal salts (such as sodium andpotassium), and alkaline earth metal salts (such as magnesium andcalcium) and organic salts. Preferred anionic salts include the halides(such as chloride salts).

[0074] “Biohydrolyzable amides” are amides of the compounds of theinvention that do not interfere with the inhibitory activity of thecompound, or that are readily converted in vivo by a mammal subject toyield an active inhibitor.

[0075] A “biohydrolyzable hydroxy imide” is an imide of a Formula (I)compound that does not interfere with the metalloprotease inhibitoryactivity of these compounds, or that is readily converted in vivo by amammal subject to yield an active Formula (I) compound. Such hydroxyimides include those that do not interfere with the biological activityof the Formula (1) compounds.

[0076] A “biohydrolyzable ester” refers to an ester of a Formula (I)compound that does not interfere with the metalloprotease inhibitoryactivity of these compounds or that is readily converted by an animal toyield an active Formula (I) compound.

[0077] A “solvate” is a complex formed by the combination of a solute(e.g., a metalloprotease inhibitor) and a solvent (e.g., water). See J.Honig et al., The Van Nostrand Chemist's Dictionary, p. 650 (1953).Pharmaceutically-acceptable solvents used according to this inventioninclude those that do not interfere with the biological activity of themetalloprotease inhibitor (e.g., water, ethanol, acetic acid,N,N-dimethylformamide and others known or readily determined by theskilled artisan).

[0078] “Optical isomer”, “stereoisomer”, “diastereomer” as referred toherein have the standard art recognized meanings (Cf., Hawley'sCondensed Chemical Dictionary, 11th Ed.).

[0079] The illustration of specific protected forms and otherderivatives of the Formula (I) compounds is not intended to be limiting.The application of other useful protecting groups, salt forms, etc. iswithin the ability of the skilled artisan.

[0080] As defined above and as used herein, substituent groups maythemselves be substituted. Such substitution may be with one or moresubstituents. Such substituents include those listed in C. Hansch and A.Leo, Substituent Constants for Correlation Analysis in Chemistry andBiology (1979), incorporated by reference herein. Preferred substituentsinclude (for example) alkyl, alkenyl, alkoxy, hydroxy, oxo, nitro,amino, aminoalkyl (e.g., aminomethyl, etc.), cyano, halo, carboxy,alkoxyaceyl (e.g., carboethoxy, etc.), thiol, aryl, cycloalkyl,heteroaryl, heterocycloalkyl (e.g., piperidinyl, morpholinyl,pyrrolidinyl, etc.), imino, thioxo, hydroxyalkyl, aryloxy, arylalkyl,and combinations thereof.

[0081] As used herein, “mammalian metalloprotease” means anymetal-containing enzyme found in mammalian sources which is capable ofcatalyzing the breakdown of collagen, gelatin or proteoglycan undersuitable assay conditions. Appropriate assay conditions can be found,for example, in U.S. Pat. No. 4,743,587, which references the procedureof Cawston, et al., Anal. Biochem. (1979) 99:340-345, use of a syntheticsubstrate is described by Weingarten. H., et al., Biochem. Biophy. Res.Comm. (1984) 139:1184-1187. Any standard method for analyzing thebreakdown of these structural proteins can, of course, be used. Themetalloprotease enzymes referred to herein are all zinc-containingproteases which are similar in structure to, for example, humanstromelysin or skin fibroblast collagenase. The ability of candidatecompounds to inhibit metalloprotease activity can, of course, be testedin the assays described above. Isolated metalloprotease enzymes can beused to confirm the inhibiting activity of the invention compounds, orcrude extracts which contain the range of enzymes capable of tissuebreakdown can be used.

[0082] Compounds:

[0083] Compounds of the invention are described in the Summary of theInvention. Preferred compounds of the invention are those in which Z isheterospiroalkylene, preferably having heteroatoms adjacent to theparent ring structure, more preferably such spiroheteroalkylenes have 4to 5 members. Preferred heteroatoms are divalent.

[0084] The invention provides compounds which are useful as inhibitorsof metalloproteases, preferably a matrix metalloproteases, and which areeffective in treating conditions characterized by excess activity ofthese enzymes. In particular, the present invention relates to acompound having a structure according to Formula (I)

[0085] wherein

[0086] R₁ is H;

[0087] R₂ is hydrogen, alkyl, or acyl;

[0088] Ar is COR₃ or SO₂R₄; and

[0089] R₃ is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl,heteroalkyl, amino, alkylamino, dialkylamino, arylamino andalkylarylamino;

[0090] R₄ is alkyl, heteroalkyl, aryl, or heteroaryl, substituted orunsubstituted;

[0091] X is O, S, SO, SO₂, or NR₅, wherein R₅ is independently chosenfrom hydrogen, alkyl, heteroalkyl, heteroaryl, aryl, SO₂R₆, COR₇, CSR₈,PO(R₉)₂ or may optionally form a ring with Y or W; and

[0092] R₆ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino;

[0093] R₇ is hydrogen, alkoxy, aryloxy, heteroaryloxy, alkyl, aryl,heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino, arylamino andalkylarylamino;

[0094] R₈ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino;

[0095] R₉ is alkyl, aryl, heteroaryl, heteroalkyl;

[0096] W is hydrogen or one or more lower alkyl moieties, or is analkylene, arylene or heteroarylene bridge between two adjacent ornonadjacent carbons (thus forming a fused ring);

[0097] Y is independently one or more of hydrogen, hydroxy, SR₁₀, SOR₄,SO₂R₄, alkoxy, amino, wherein amino is of formula NR₁₁,R₁₂, wherein R₁₁and R₁₂ are independently chosen from hydrogen, alkyl, heteroalkyl,heteroaryl, aryl, SO₂R₆, COR₇, CSR₈, PO(R₉)₂; and

[0098] R₁₀ is hydrogen, alkyl, aryl, heteroaryl;

[0099] Z is nil, a spiro moiety or an oxo group substituted on theheterocyclic ring;

[0100] n is 1-4.

[0101] This structure also includes an optical isomer, diastereomer orenantiomer for Formula (I), or a pharmaceutically-acceptable salt, orbiohydrolyzable ester, amide, or imide thereof.

[0102] Compound Preparation:

[0103] The hydroxamic compounds of Formula (I) can be prepared using avariety of procedures. General schemes include the following.

[0104] Preparation of the Y Moiety

[0105] For the manipulation of Y it is understood that the skilledartisan may choose to prepare Y before, after or concurrent with thepreparation of the heterocyclic ring. For clarity, the W and Z moietyare not shown below. More than one Y and Z may be present in thecompounds of formula (I). For compounds where Y is not adjacent to thering nitrogen, a preferred method of making the compounds is;

[0106] Where R is a derivatizable group or can be manipulated orsubstituted, such compounds are known or are prepared by known methods.(A) is converted to its analogous sultamester and R is manipulated togive (B) during this or a subsequent step. Y and Z can be added oraltered, followed by appropriate reaction to provide R₁. For example,this step may include treatment with hydroxyl amine under basicconditions to give a compound of formula I (C).

[0107] For the preparation and elaboration of the heterocyclic ring itis understood that the skilled artisan may choose to prepare Y before,after or concurrent with the preparation of the heterocyclic ring. Forclarity, the W, Y. and Z moiety are not shown below. More than one W, Yand Z may be present in the compounds of formula (I). For compoundswhere X is nitrogen, the preferred method for the manipulation of R₅ isshown. In the scheme below. L is any acceptable leaving group, and B isa blocking group as above. The skilled artisan will recognize that thechoice of blocking group is within the skill of the artisan working inorganic chemistry.

[0108] For compounds containing two different groups attached to thering nitrogens the preferred methods of ring formation are shown. Forthe preparation and elaboration of the heterocyclic ring it isunderstood that the skilled artisan may choose to prepare Y before,after or concurrent with the preparation of the heterocyclic ring. Forclarity, the W, Y. and Z moiety are not shown below. More than one W, Yand Z may be present in the compounds of formula (I). The protecteddiamine is treated with the sulfonyl halide. Removal of the protectinggroup followed by addition of R₅L. Addition of a pyruvate or glyoxylategroup under standard conditions closes the ring to form the heterocycle.Upon formation of the ring, elaboration of the invention proceeds asdescribed above.

[0109] For compounds containing an oxygen or a sulfur in theheterocyclic ring the preferred methods of ring formation are shown. Forthe preparation and elaboration of the heterocyclic ring it isunderstood that the skilled artisan may choose to prepare Y before,after or concurrent with the preparation of the heterocyclic ring. Forclarity, the W. Y. and Z moiety are not shown below. More than one W, Yand Z may be present in the compounds of formula (I). A bifunctionalmoiety, for example an amino alcohol or an amino thiol is reacted withan sulfonyl halide as shown below. The halo moiety serves as a leavinggroup. Addition of a pyruvate or glyoxylate group under standardconditions closes the ring to form the heterocycle. Upon formation ofthe ring, elaboration of the invention proceeds as described above.

[0110] Preparation of the Z Moiety

[0111] Of course the skilled artisan will recognize that schemesapplicable to the preparation of Y may be useful in the preparation of Zas noted above. Other preferred methods are provided for the reader.

[0112] Where Z is a ketal or thioketal the compounds of the inventionmay be prepared from a compound having a carbonyl in the ring. Suchcompounds are prepared by known methods, and many of such compounds areknown or commercially available. Thus the skilled artisan willappreciate that a hydroxy, amino, imino, alkoxy, oxo or any other groupthat may be manipulated into a carbonyl compound. The order ofelaborating the ketal, R₁ or the sultamester may be changed.

[0113] A preferred method of making the spiro compounds of the inventionis via a carbonyl compound, using “protecting group” technology known inthe art, such as a thioketal or ketal, and the like. Ketals, acetals andthe like are prepared from carbonyl compounds by methods known in theart. Such carbonyl compounds can be made of cyclic hydroxy alkyleneamines via oxidation to a ketone, or of lactams, which provide for2-amino spiro functionality.

[0114] A variety of compounds can be generated in a similar fashion,using the guidance of the scheme above.

[0115] In the above schemes, where R′ is alkoxy or alkylthio, thecorresponding hydroxy or thiol compounds are derived from the finalcompounds by using a standard dealkylating procedure (Bhatt, et al.,“Cleavage of Ethers”, Synthesis, 1983, pp. 249-281).

[0116] These steps may be varied to increase yield of desired product.The skilled artisan will also recognize the judicious choice ofreactants, solvents, and temperatures is an important component insuccessful synthesis. While the determination of optimal conditions,etc. is routine, it will be understood that to make a variety ofcompounds can be generated in a similar fashion, using the guidance ofthe scheme above.

[0117] The starting materials used in preparing the compounds of theinvention are known, made by known methods, or are commerciallyavailable as a starting material.

[0118] It is recognized that the skilled artisan in the art of organicchemistry can readily carry out standard manipulations of organiccompounds without further direction, that is, it is well within thescope and practice of the skilled artisan to carry out suchmanipulations. These include, but are not limited to, reduction ofcarbonyl compounds to their corresponding alcohols, oxidations ofhydroxyls and the like, acylations, aromatic substitutions, bothelectrophilic and nucleophilic, etherifications, esterification andsaponification and the like. Examples of these manipulations arediscussed in standard texts such as March, Advanced Organic Chemistry(Wiley). Carey and Sundberg, Advanced Organic Chemistry (Vol. 2) andKeeting, Heterocyclic Chemistry (all 17 volumes).

[0119] The skilled artisan will readily appreciate that certainreactions are best carried out when other functionality is masked orprotected in the molecule, thus avoiding any undesirable side reactionsand/or increasing the yield of the reaction. Often the skilled artisanutilizes protecting groups to accomplish such increased yields or toavoid the undesired reactions. These reactions are found in theliterature and are also well within the scope of the skilled artisan.Examples of many of these manipulations can be found for example in T.Greene, Protecting Groups in Organic Synthesis. Of course, amino acidsused as starting materials with reactive side chains are preferablyblocked to prevent undesired side reactions.

[0120] The compounds of the invention may have one or more chiralcenters. As a result, one may selectively prepare one optical isomer,including diastereomer and enantiomer, over another, for example bychiral starting materials, catalysts or solvents, or may prepare bothstereoisomers or both optical isomers, including diastereomers andenantiomers at once (a racemic mixture). Since the compounds of theinvention may exist as racemic mixtures, mixtures of optical isomers,including diastereomers and enantiomers, or stereoisomers may beseparated using known methods, such as chiral salts, chiralchromatography and the like.

[0121] In addition, it is recognized that one optical isomer, includingdiastereomer and enantiomer, or stereoisomer may have favorableproperties over the other. Thus when disclosing and claiming theinvention, when one racemic mixture is disclosed, it is clearlycontemplated that both optical isomers, including diastereomers andenantiomers, or stereoisomers substantially free of the other aredisclosed and claimed as well.

[0122] Methods of Use

[0123] Metalloproteases (MPs) found in the body operate, in part, bybreaking down the extracellular matrix, which comprises extracellularproteins and glycoproteins. These proteins and glycoproteins play animportant role in maintaining the size, shape, structure and stabilityof tissue in the body. Inhibitors of metalloproteases are useful intreating diseases caused, at least in part, by breakdown of suchproteins. It is known that MPs are intimately involved in tissueremodeling. As a result of this activity they have been said to beactive in many disorders involving either the:

[0124] breakdown of tissues; including degenerative diseases, such asarthritis, multiple sclerosis and the like; metastasis or mobility oftissues in the body:

[0125] the remodeling of tissues, including fibrotic disease, scarring,benign hyperplasia, and the like.

[0126] The compounds of the present invention treat disorders, diseasesand/or unwanted conditions which are characterized by unwanted orelevated activity by that class of proteases. For example the compoundscan be used to inhibit proteases which

[0127] destroy structural proteins (i.e. the proteins that maintaintissue stability and structure);

[0128] interfere in inter/intracellular signaling, including thoseimplicated in cytokine up-regulation, and/or cytokine processing and/orinflammation, tissue degradation and other maladies [Mohler K M, et al,Nature 370 (1994) 218-220, Gearing A J H, et al, Nature 370 (1994)555-557 McGeehan G M, et al. Nature 370 (1994) 558-561], and/or

[0129] facilitate processes which are undesired in the subject beingtreated, for example, the processes of sperm maturation, eggfertilization and the like.

[0130] As used herein, a “MP related disorder” or “a MP related disease”is one that involves unwanted or elevated MP activity in the biologicalmanifestation of the disease or disorder; in the biological cascadeleading to the disorder; or as a symptom of the disorder. This“involvement” of the MP includes;

[0131] The unwanted or elevated MP activity as a “cause” of the disorderor biological manifestation, whether the activity was elevatedgenetically, by infection, by autoimmunity, trauma, biomechanicalcauses, lifestyle [e.g. obesity] or by some other cause;

[0132] The MP as part of the observable manifestation of the disease ordisorder. That is, the disease or disorder is measurable in terms of theincreased MP activity, or from a clinical standpoint, unwanted orelevated MP levels indicate the disease. MPs need not be the “hallmark”of the disease or disorder;

[0133] The unwanted or elevated MP activity is part of the biochemicalor cellular cascade that results or relates to the disease or disorder.In this respect, inhibition of the MP activity interrupts the cascade,and thus controls the disease.

[0134] Advantageously, many MPs are not distributed evenly throughoutthe body. Thus the distribution of MPs expressed in various tissues areoften specific to those tissues. For example, the distribution ofmetalloproteases implicated in the breakdown of tissues in the joints,is not the same as the distribution of metalloproteases found in othertissues. Thus, though not essential for activity or efficacy, certaindisorders preferably are treated with compounds that act on specific MPsfound in the affected tissues or regions of the body. For example, acompound which displays a higher degree of affinity and inhibition for aMP found in the joints (e.g. chondrocytes) would be preferred fortreatment of disease found there than other compounds which are lessspecific.

[0135] In addition, certain inhibitors are more bioavailable to certaintissues than others, and this judicious choice of inhibitor, with theselectivity described above provides for specific treatment of thedisorder, disease or unwanted condition. For example, compounds of thisinvention vary in their ability to penetrate into the central nervoussystem. Thus compounds may be selected to produce effects mediatedthrough MPs found specifically outside the central nervous system.

[0136] Determination of the specificity of a MP inhibitor of a certainMP is within the skill of the artisan in that field. Appropriate assayconditions can be found in the literature. Specifically assays are knownfor stromelysin and collagenase. For example, U.S. Pat. No. 4,743,587references the procedure of Cawston, et al., Anal Biochem (1979)99:340-345. The use of a synthetic substrate in an assay is described byWeingarten, H., et al., Biochem Biophy Res Comm (1984) 139:1184-1187.Any standard method for analyzing the breakdown of structural proteinsby MPs can, of course, be used. The ability of compounds of theinvention to inhibit metalloprotease activity can, of course, be testedin the assays found in the literature, or variations thereof. Isolatedmetalloprotease enzymes can be used to confirm the inhibiting activityof the invention compounds, or crude extracts which contain the range ofenzymes capable of tissue breakdown can be used.

[0137] As a result of the MP inhibitory effect of the compounds of theinvention, the compounds of the invention are also useful in treatingthe following disorders by virtue of their metalloprotease activity.

[0138] The compounds of this invention are also useful for theprophylactic or acute treatment. They are administered in any way theskilled artisan in the fields of medicine or pharmacology would desire.It is immediately apparent to the skilled artisan that preferred routesof administration will depend upon the disease state being treated, andthe dosage form chosen. Preferred routes for systemic administrationinclude administration perorally or parenterally.

[0139] However, the skilled artisan will readily appreciate theadvantage of administering the MP inhibitor directly to the affectedarea for many disorders. For example, it may be advantageous toadminister MP inhibitors directly to the area of the disease orcondition as in area affected by surgical trauma (e.g., angioplasty),area affected by scarring or burn (e.g., topical to the skin),

[0140] Because the remodeling of bone involves MPs, the compounds of theinvention are useful in preventing prosthesis loosening. It is known inthe art that over time prostheses loosen, become painful, and may resultin further bone injury, thus demanding replacement. The need forreplacement of such prostheses includes those such as in, jointreplacements (for example hip, knee and shoulder replacements), dentalprosthesis, including dentures, bridges and prosthesis secured to themaxilla and/or mandible.

[0141] MPs are also active in remodeling of the cardiovascular system(for example, in congestive heart failure). It has been suggested thatone of the reasons angioplasty has a higher than expected long termfailure rate (reclosure over time) is that MP activity is not desired oris elevated in response to what may be recognized by the body as“injury” to the basement membrane of the vessel. Thus regulation of MPactivity in indications such as dilated cardiomyopathy, congestive heartfailure, atherosclerosis, plaque rupture, reperfusion injury, ischemia,chronic obstructive pulmonary disease, angioplasty restenosis and aorticaneurysm may increase long term success of any other treatment, or maybe a treatment in itself.

[0142] In skin care, MPs are implicated in the remodeling or “turnover”of skin. As a result, the regulation of MPs improves treatment of skinconditions including but not limited to, wrinkle repair, regulation andprevention and repair of ultraviolet induced skin damage. Such atreatment includes prophylactic treatment or treatment before thephysiological manifestations are obvious. For example, the MP may beapplied as a pre-exposure treatment to prevent ultraviolet, damageand/or during or after exposure to prevent or minimize post-exposuredamage. In addition, MPs are implicated in skin disorders and diseasesrelated to abnormal tissues that result from abnormal turnover, whichincludes metalloprotease activity, such as epidermolysis bullosa,psoriasis, scleroderma and atopic dermatitis. The compounds of theinvention are also useful for treating the consequences of “normal”injury to the skin including scarring or “contraction” of tissue, forexample, following burns. MP inhibition is also useful in surgicalprocedures involving the skin for prevention of scarring, and promotionof normal tissue growth including in such applications as limbreattachment and refractory surgery (whether by laser or incision).

[0143] In addition. MPs are related to disorders involving irregularremodeling of other tissues, such as bone, for example, in otosclerosisand/or osteoporosis, or for specific organs, such as in liver cirrhosisand fibrotic lung disease. Similarly in diseases such as multiplesclerosis, MPs may be involved in the irregular modeling of blood brainbarrier and/or myelin sheaths of nervous tissue. Thus regulating MPactivity may be used as a strategy in treating, preventing, andcontrolling such diseases.

[0144] MPs are also thought to be involved in many infections, includingcytomegalovirus; [CMV] retinitis; HIV, and the resulting syndrome, AIDS.

[0145] MPs may also be involved in extra vascularization wheresurrounding tissue needs to be broken down to allow new blood vesselssuch as in angiofibroma and hemangioma.

[0146] Since MPs break down the extracellular matrix, it is contemplatedthat inhibitors of these enzymes can be used as birth control agents,for example in preventing ovulation, in preventing penetration of thesperm into and through the extracellular milieu of the ovum,implantation of the fertilized ovum and in preventing sperm maturation.

[0147] In addition they are also contemplated to be useful in preventingor stopping premature labor and delivery.

[0148] Since MPs are implicated in the inflammatory response, and in theprocessing of cytokines the compounds are also useful asanti-inflammatories, for use in disease where inflammation is prevalentincluding, inflammatory bowel disease, Crohn's disease, ulcerativecolitis, pancreatitis, diverticulitis, asthma or related lung disease,rheumatoid arthritis, gout and Reiter's Syndrome.

[0149] Where autoimmunity is the cause of the disorder, the immuneresponse often triggers MP and cytokine activity. Regulation of MPs intreating such autoimmune disorders is a useful treatment strategy. ThusMP inhibitors can be used for treating disorders including, lupuserythmatosis, ankylosing spondylitis, and autoimmune keratitis.Sometimes the side effects of autoimmune therapy result in exacerbationof other conditions mediated by MPs, here MP inhibitor therapy iseffective as well, for example, in autoimmune-therapy-induced fibrosis.

[0150] In addition, other fibrotic diseases lend themselves to this typeof therapy, including pulmonary disease, bronchitis, emphysema, cysticfibrosis, acute respiratory distress syndrome (especially the acutephase response).

[0151] Where MPs are implicated in the undesired breakdown of tissue byexogenous agents, these can be treated with MP inhibitors. For example,they are effective as rattle snake bite antidote, as anti-vessicants, intreating allergic inflammation, septicemia and shock. In addition, theyare useful as antiparasitics (e.g., in malaria) and antiinfectives. Forexample, they are thought to be useful in treating or preventing viralinfection, including infection which would result in herpes, “cold”(e.g., rhinoviral infection), meningitis, hepatitis, HIV infection andAIDS.

[0152] MP inhibitors are also thought to be useful in treatingAlzheimer's disease, amyotrophic lateral sclerosis (ALS), musculardystrophy, complications resulting from or arising out of diabetes,especially those involving loss of tissue viability, coagulation, Graftvs. Host disease, leukemia, cachexia, anorexia, proteinuria, and perhapsregulation of hair growth.

[0153] For some diseases, conditions or disorders MP inhibition iscontemplated to be a preferred method of treatment. Such diseases,conditions or disorders include, arthritis (including osteoarthritis andrheumitoid arthritis), cancer (especially the prevention or arrest oftumor growth and metastasis), ocular disorders (especially cornealulceration, lack of corneal healing, macular degeneration, andpterygium), arid gum disease (especially periodontal disease, andgingivitis)

[0154] Compounds preferred for, but not limited to, the treatment ofarthritis (including osteoarthritis and rheumatoid arthritis) are thosecompounds that are selective for the metalloproteases and thedisintegrin metalloproteases.

[0155] Compounds preferred for, but not limited to, the treatment ofcancer (especially the prevention or arrest of tumor growth andmetastasis) are those compounds that preferentially inhibit gelatinasesor type IV collagenases.

[0156] Compounds preferred for, but not limited to, the treatment ofocular disorders (especially corneal ulceration, lack of cornealhealing, macular degeneration, and pterygium) are those compounds thatbroadly inhibit metalloproteases. Preferably these compounds areadministered topically, more preferably as a drop or gel.

[0157] Compounds preferred for, but not limited to, the treatment of gumdisease (especially periodontal disease, and gingivitis) are thosecompounds that preferentially inhibit collagenases.

[0158] Compositions:

[0159] The compositions of the invention comprise:

[0160] (a) a safe and effective amount of a compound of Formula (I); and

[0161] (b) a pharmaceutically-acceptable carrier.

[0162] As discussed above, numerous diseases are known to be mediated byexcess or undesired metalloprotease activity. These include tumormetastasis, osteoarthritis, rheumatoid arthritis, skin inflammation,ulcerations, particularly of the cornea, reaction to infection,periodontitis and the like. Thus, the compounds of the invention areuseful in therapy with regard to conditions involving this unwantedactivity.

[0163] The invention compounds can therefore be formulated intopharmaceutical compositions for use in treatment or prophylaxis of theseconditions. Standard pharmaceutical formulation techniques are used,such as those disclosed in Remington's Pharmaceutical Sciences, MackPublishing Company, Easton, Pa., latest edition.

[0164] A “safe and effective amount” of a Formula (I) compound is anamount that is effective, to inhibit metalloproteases at the site(s) ofactivity, in a mammal subject, without undue adverse side effects (suchas toxicity, irritation, or allergic response), commensurate with areasonable benefit/risk ratio when used in the manner of this invention.The specific “safe and effective amount” will, obviously, vary with suchfactors as the particular condition being treated, the physicalcondition of the patient, the duration of treatment, the nature ofconcurrent therapy (if any), the specific dosage form to be used, thecarrier employed, the solubility of the Formula (I) compound therein,and the dosage regimen desired for the composition.

[0165] In addition to the subject compound, the compositions of thesubject invention contain a pharmaceutically-acceptable carrier. Theterm “pharmaceutically-acceptable carrier”, as used herein, means one ormore compatible solid or liquid filler diluents or encapsulatingsubstances which are suitable for administration to a mammal. The term“compatible”, as used herein, means that the components of thecomposition are capable of being commingled with the subject compound,and with each other, in a manner such that there is no interaction whichwould substantially reduce the pharmaceutical efficacy of thecomposition under ordinary use situations. Pharmaceutically-acceptablecarriers must, of course, be of sufficiently high purity andsufficiently low toxicity to render them suitable for administration tothe aminal, preferably mammal being treated.

[0166] Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose: starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt, gelatin: talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glcol; alginic acid: emulsifiers, such as theTWEENS; wetting agents, such sodium lauryl sulfate, coloring agents;flavoring agents, tableting agents, stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

[0167] The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

[0168] If the subject compound is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with blood-compatible suspending agent, the pH of which has beenadjusted to about 7,4.

[0169] In particular, pharmaceutically-acceptable carriers for systemicadministration include sugars, starches, cellulose and its derivatives,malt, gelatin, talc, calcium sulfate, vegetable oils, synthetic oils,polyols, alginic acid, phosphate buffer solutions, emulsifiers, isotonicsaline, and pyrogen-free water. Preferred carriers for parenteraladministration include propylene glycol, ethyl oleate, pyrrolidone,ethanol, and sesame oil. Preferably, the pharmaceutically-acceptablecarrier, in compositions for parenteral administration, comprises atleast about 90% by weight of the total composition.

[0170] The compositions of this invention are preferably provided inunit dosage form. As used herein, a “unit dosage form” is a compositionof this invention containing an amount of a Formula (I) compound that issuitable for administration to a aminal, preferably mammal subject, in asingle dose, according to good medical practice. These compositionspreferably contain from about 5 mg (milligrams) to about 1000 mg, morepreferably from about 10 mg to about 500 mg, more preferably from about10 mg to about 300 mg, of a Formula (I) compound.

[0171] The compositions of this invention may be in any of a variety offorms, suitable (for example) for oral, rectal, topical, nasal, ocularor parenteral administration. Depending upon the particular route ofadministration desired, a variety of pharmaceutically-acceptablecarriers well-known in the art may be used. These include solid orliquid fillers, diluents, hydrotropes, surface-active agents, andencapsulating substances. Optional pharmaceutically-active materials maybe included, which do not substantially interfere with the inhibitoryactivity of the Formula (I) compound. The amount of carrier employed inconjunction with the Formula (I) compound is sufficient to provide apractical quantity of material for administration per unit dose of theFormula (I) compound. Techniques and compositions for making dosageforms useful in the methods of this invention are described in thefollowing references, all incorporated by reference herein: ModernPharmaceutics, Chapters 9 and 10 (Banker & Rhodes, editors, 1979);Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); andAnsel, Introduction to Pharmaceutical Dosage Forms 2d Edition (1976).

[0172] In addition to the subject compound, the compositions of thesubject invention contain a pharmaceutically-acceptable carrier. Theterm “pharmaceutically-acceptable carrier”, as used herein, means one ormore compatible solid or liquid filler diluents or encapsulatingsubstances which are suitable for administration to a aminal, preferablymammal. The term “compatible”, as used herein, means that the componentsof the composition are capable of being commingled with the subjectcompound, and with each other, in a manner such that there is nointeraction which would substantially reduce the pharmaceutical efficacyof the composition under ordinary use situations.Pharmaceutically-acceptable carriers must, of course, be of sufficientlyhigh purity and sufficiently low toxicity to render them suitable foradministration to the aminal, preferably mammal being treated.

[0173] Some examples of substances which can serve aspharmaceutically-acceptable carriers or components thereof are sugars,such as lactose, glucose and sucrose; starches, such as corn starch andpotato starch; cellulose and its derivatives, such as sodiumcarboxymethyl cellulose, ethyl cellulose, and methyl cellulose; powderedtragacanth; malt; gelatin; talc; solid lubricants, such as stearic acidand magnesium stearate; calcium sulfate; vegetable oils, such as peanutoil, cottonseed oil, sesame oil, olive oil, corn oil and oil oftheobroma; polyols such as propylene glycol, glycerine, sorbitol,mannitol, and polyethylene glycol; alginic acid; emulsifiers, such asthe TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents;flavoring agents; tableting agents; stabilizers; antioxidants;preservatives; pyrogen-free water; isotonic saline; and phosphate buffersolutions.

[0174] The choice of a pharmaceutically-acceptable carrier to be used inconjunction with the subject compound is basically determined by the waythe compound is to be administered.

[0175] If the subject compound is to be injected, the preferredpharmaceutically-acceptable carrier is sterile, physiological saline,with blood-compatible suspending agent, the pH of which has beenadjusted to about 7.4.

[0176] Various oral dosage forms can be used, including such solid formsas tablets, capsules, granules and bulk powders. These oral formscomprise a safe and effective amount, usually at least about 5%, andpreferably from about 25% to about 50%, of the Formula (I) compound.Tablets can be compressed, tablet triturates, enteric-coated,sugar-coated, film-coated, or multiple-compressed, containing suitablebinders, lubricants, diluents, disintegrating agents, coloring agents,flavoring agents, flow-inducing agents, and melting agents. Liquid oraldosage forms include aqueous solutions, emulsions, suspensions,solutions and/or suspensions reconstituted from non-effervescentgranules, and effervescent preparations reconstituted from effervescentgranules, containing suitable solvents, preservatives, emulsifyingagents, suspending agents, diluents, sweeteners, melting agents,coloring agents and flavoring agents.

[0177] The pharmaceutically-acceptable carrier suitable for thepreparation of unit dosage forms for peroral administration arewell-known in the art. Tablets typically comprise conventionalpharmaceutically-compatible adjuvants as inert diluents, such as calciumcarbonate, sodium carbonate, mannitol, lactose and cellulose; binderssuch as starch, gelatin and sucrose; disintegrants such as starch,alginic acid and croscarmnelose; lubricants such as magnesium stearate,stearic acid and talc. Glidants such as silicon dioxide can be used toimprove flow characteristics of the powder mixture. Coloring agents,such as the FD&C dyes, can be added for appearance. Sweeteners andflavoring agents, such as aspartame, saccharin, menthol, peppermint, andfruit flavors, are useful adjuvants for chewable tablets. Capsulestypically comprise one or more solid diluents disclosed above. Theselection of carrier components depends on secondary considerations liketaste, cost, and shelf stability, which are not critical for thepurposes of the subject invention, and can be readily made by a personskilled in the art.

[0178] Peroral compositions also include liquid solutions, emulsions,suspensions, and the like. The pharmaceutically-acceptable carrierssuitable for preparation of such compositions are well known in the art.Typical components of carriers for syrups, elixirs, emulsions andsuspensions include ethanol, glycerol, propylene glycol, polyethyleneglycol, liquid sucrose, sorbitol and water. For a suspension, typicalsuspending agents include methyl cellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth and sodium alginate; typicalwetting agents include lecithin and polysorbate 80; and typicalpreservatives include methyl paraben and sodium benzoate. Peroral liquidcompositions may also contain one or more components such as sweeteners,flavoring agents and colorants disclosed above.

[0179] Such compositions may also be coated by conventional methods,typically with pH or time-dependent coatings, such that the subjectcompound is released in the gastrointestinal tract in the vicinity ofthe desired topical application, or at various times to extend thedesired action. Such dosage forms typically include, but are not limitedto, one or more of cellulose acetate phthalate, polyvinylacetatephthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose,Eudragit coatings, waxes and shellac.

[0180] Compositions of the subject invention may optionally includeother drug actives.

[0181] Other compositions useful for attaining systemic delivery of thesubject compounds include sublingual, buccal and nasal dosage forms.Such compositions typically comprise one or more of soluble fillersubstances such as sucrose, sorbitol and mannitol; and binders such asacacia, microcrystalline cellulose, carboxymethyl cellulose andhydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners,colorants, antioxidants and flavoring agents disclosed above may also beincluded.

[0182] The compositions of this invention can also be administeredtopically to a subject, e.g., by the direct laying on or spreading ofthe composition on the epidermal or epithelial tissue of the subject, ortransdermally via a “patch”. Such compositions include, for example,lotions, creams, solutions, gels and solids. These topical compositionspreferably comprise a safe and effective amount, usually at least about0.1%, and preferably from about 1% to about 5%, of the Formula (I)compound. Suitable carriers for topical administration preferably remainin place on the skin as a continuous film, and resist being removed byperspiration or immersion in water. Generally, the carrier is organic innature and capable of having dispersed or dissolved therein the Formula(I) compound. The carrier may include pharmaceutically-acceptableemolients, emulsifiers, thickening agents, solvents and the like.

[0183] Methods of Administration:

[0184] This invention also provides methods of treating or preventingdisorders associated with excess or undesired metalloprotease activityin an animal, preferably mammal subject, by administering a safe andeffective amount of a Formula (I) compound to said subject. As usedherein, a “disorder associated with excess or undesired metalloproteaseactivity” is any disorder characterized by degradation of proteins. Themethods of the invention are useful in treating disorders such as (forexample) osteoarthritis, periodontitis, corneal ulceration, tumorinvasion, and rheumatoid arthritis.

[0185] The Formula (I) compounds and compositions of this invention canbe administered topically or systemically. Systemic application includesany method of introducing Formula (I) compound into the tissues of thebody, e.g., intra-articular (especially in treatment of rheumatoidarthritis), intrathecal, epidural, intramuscular, transdermal,intravenous, intraperitoneal, subcutaneous, sublingual, rectal, and oraladministration. The Formula (I) compounds of the present invention arepreferably administered orally.

[0186] The specific dosage of inhibitor to be administered, as well asthe duration of treatment, and whether the treatment is topical orsystemic are interdependent. The dosage and treatment regimen will alsodepend upon such factors as the specific Formula (I) compound used, thetreatment indication, the ability of the Formula (I) compound to reachminimum inhibitory concentrations at the site of the metalloprotease tobe inhibited, the personal attributes of the subject (such as weight),compliance with the treatment regimen, and the presence and severity ofany side effects of the treatment.

[0187] Typically, for a human adult (weighing approximately 70kilograms), from about 5 mg to about 3000 mg, more preferably from about5 mg to about 1000 mg, more preferably from about 10 mg to about 100 mg,of Formula (I) compound are administered per day for systemicadministration. It is understood that these dosage ranges are by way ofexample only, and that daily administration can be adjusted depending onthe factors listed above.

[0188] A preferred method of administration for treatment of rheumatoidarthritis is oral or parenterally via intra-articular injection. As isknown and practiced in the art, all formulations for parenteraladministration must be sterile. For mammals, especially humans,(assuming an approximate body weight of 70 kilograms) individual dosesof from about 10 mg to about 1000 mg are preferred.

[0189] A preferred method of systemic administration is oral. Individualdoses of from about 10 mg to about 1000 mg, preferably from about 10 mgto about 300 mg are preferred.

[0190] Topical administration can be used to deliver the Formula (I)compound systemically, or to treat a subject locally. The amounts ofFormula (I) compound to be topically administered depends upon suchfactors as skin sensitivity, type and location of the tissue to betreated, the composition and carrier (if any) to be administered, theparticular Formula (I) compound to be administered, as well as theparticular disorder to be treated and the extent to which systemic (asdistinguished from local) effects are desired.

[0191] The inhibitors of the invention can be targeted to specificlocations where the metalloprotease is accumulated by using targetingligands. For example, to focus the inhibitors to metalloproteasecontained in a tumor, the inhibitor is conjugated to an antibody orfragment thereof which is immunoreactive with a tumor marker as isgenerally understood in the preparation of immunotoxins in general. Thetargeting ligand can also be a ligand suitable for a receptor which ispresent on the tumor. Any targeting ligand which specifically reactswith a marker for the intended target tissue can be used. Methods forcoupling the invention compound to the targeting ligand are well knownand are similar to those described below for coupling to carrier. Theconjugates are formulated and administered as described above.

[0192] For localized conditions, topical administration is preferred.For example, to treat ulcerated cornea, direct application to theaffected eye may employ a formulation as eyedrops or aerosol. Forcorneal treatment, the compounds of the invention can also be formulatedas gels, drops or ointments, or can be incorporated into collagen or ahydrophilic polymer shield. The materials can also be inserted as acontact lens or reservoir or as a subconjunctival formulation. Fortreatment of skin inflammation, the compound is applied locally andtopically, in a gel, paste, salve or ointment. The mode of treatmentthus reflects the nature of the condition and suitable formulations forany selected route are available in the art.

[0193] In all of the foregoing, of course, the compounds of theinvention can be administered alone or as mixtures, and the compositionsmay further include additional drugs or excipients as appropriate forthe indication.

[0194] Some of the compounds of the invention also inhibit bacterialmetalloproteases although generally at a lower level than that exhibitedwith respect to mammalian metalloproteases. Some bacterialmetalloproteases seem to be less dependent on the stereochemistry of theinhibitor, whereas substantial differences are found betweendiastereomers in their ability to inactivate the mammalian proteases.Thus, this pattern of activity can be used to distinguish between themammalian and bacterial enzymes.

[0195] Preparation and Use of Antibodies:

[0196] The invention compounds can also be utilized in immunizationprotocols to obtain antisera immunospecific for the invention compounds.As the invention compounds are relatively small, they are advantageouslycoupled to antigenically neutral carriers such as the conventionallyused keyhole limpet hemocyanin (KLH) or serum albumin carriers. Forthose invention compounds having a carboxyl functionality, coupling tocarrier can be done by methods generally known in the art. For example,the carboxyl residue can be reduced to an aldehyde and coupled tocarrier through reaction with sidechain amino groups in protein-basedcarriers, optionally followed by reduction of imino linkage formed. Thecarboxyl residue can also be reacted with sidechain amino groups usingcondensing agents such as dicyclohexyl carbodiimide or othercarbodiimide dehydrating agents.

[0197] Linker compounds can also be used to effect the coupling; bothhomobifunctional and heterobifunctional linkers are available fromPierce Chemical Company. Rockford, Ill. The resulting immunogeniccomplex can then be injected into suitable mammalian subjects such asmice, rabbits, and the like. Suitable protocols involve repeatedinjection of the immunogen in the presence of adjuvants according to aschedule which boosts production of antibodies in the serum. The titersof the immune serum can readily be measured using immunoassayprocedures, now standard in the art, employing the invention compoundsas antigens.

[0198] The antisera obtained can be used directly or monoclonalantibodies may be obtained by harvesting the peripheral bloodlymphocytes or the spleen of the immunized animal and immortalizing theantibody-producing cells, followed by identifying the suitable antibodyproducers using standard immunoassay techniques.

[0199] The polyclonal or monoclonal preparations are then useful inmonitoring therapy or prophylaxis regimens involving the compounds ofthe invention. Suitable samples such as those derived from blood, serum,urine, or saliva can be tested for the presence of the administeredinhibitor at various times during the treatment protocol using standardimmunoassay techniques which employ the antibody preparations of theinvention.

[0200] The invention compounds can also be coupled to labels such asscintigraphic labels, e.g., technetium 99 or I-131, using standardcoupling methods. The labeled compounds are administered to subjects todetermine the locations of excess amounts of one or moremetalloproteases in vivo. The ability of the inhibitors to selectivelybind metalloprotease is thus taken advantage of to map the distributionof these enzymes in situ. The techniques can also be employed inhistological procedures and the labeled invention compounds can be usedin competitive immunoassays.

[0201] The following non-limiting examples illustrate the compounds,compositions, and uses of the present invention.

EXAMPLES

[0202] Compounds are analyzed using ¹H and ¹³C NMR, Elemental analysis,mass spectra and/or IR spectra, as appropriate.

[0203] Typically inert solvents are used, preferably in dried form. Forexample, tetrahydrofuran (THF) is distilled from sodium andbenzophenone, diisopropylamine is distilled from calcium hydride and allother solvents are purchased as the appropriate grade. Chromatography isperformed on silica gel (70-230 mesh; Aldrich) or (230-400 mesh; Merck)as appropriate. Thin layer chromatography analysis (TLC) is performed onglass mounted silica gel plates (200-300 mesh; Baker) and visualizedwith UV or 5% phosphomolybdic acid in EtOH.

EXAMPLE 1

[0204] Synthesis ofN-hydroxy-1,3-di-[(4-methoxyphenyl)sulfonyl]-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide(1c).

[0205] 1,3-Di-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-propane (1a):2,2-Dimethyl-1,3-propanediamine (502 mg, 4.9 mmol) is dissolved in 1:1water:dioxane (80 mL). To this is added 4-methoxyphenylsulfonyl chloride(2.03 g, 9.8 mmol) followed by 4-methylmorpholine (2.4 mL, 21.6 mmol).This mixture is stirred 30 minutes at room temperature at which time TLC(7:3 ethyl acetate:hexane) indicated the reaction to be complete. Thereaction is diluted with 150 mL water and the product is extracted intoethyl acetate, dried, and evaporated to give1,3-di-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-propane as an off-whitesolid: mp 115-117° C.

[0206] Methyl1,3-di-[(4-methoxyphenyl)sulfonyl]-5,5-dimethyl-hexahydro-pyrimidine-2-carboxylate(lb): 1,3-Di-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-propane (991 mg,2.2 mmol) is combined with a 0.55M solution of methyl glyoxylate (12.2mL, 6.7 mmol) in ether and the ether is removed under reduced pressure.Benzene (75 mL) is then added followed by a catalytic amount of sulfuricacid and the mixture is heated at reflux with Dean-Stark removal ofwater/bezene for 15 minutes, at which time TLC (1:1 ethylacetate:hexane) indicates the reaction to be complete. The mixture iscooled, washed with water, dried (Na₂SO₄) and concentrated in vacuo togive methyl1,3-di-[(4-methoxyphenyl)sulfonyl]-5,5-dimethyl-hexahydro-pyrimidine-2-carboxylateas an oil.

[0207]N-hydroxy-1,3-di-[(4-methoxyphenyl)sulfonyl]-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide(1c): Methyl1,3-di-[(4-methoxyphenyl)sulfonyl]-5,5-dimethyl-hexahydro-pyrimidine-2-carboxylate(826 mg, 1.6 mmol) is treated with 4.6 mL of NH₂OK (1.76 M in methanol,solution prepared as described in Fieser and Fieser, Vol. 1, p. 478).The reaction is stirred for 16 hours at room temperature and neutralizedwith 1M aqueous hydrochloric acid. The volatiles are removed underreduced pressure and the residue is partitioned between ethyl acetateand water. The organic extracts are washed with brine, dried (Na₂SO₄)and concentrated in vacuo to give a white solid. The crude product ispurified by crystallization from ethanol to give theN-hydroxy-1,3-di-[(4-methoxyphenyl)su[fonyl]-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide. MP 125-126° C.MS(ES): 514 [M+H]⁻.

EXAMPLE 2

[0208] The following compounds are prepared similarly to Example 1:

[0209]N-Hydroxy-1,3-di-[(4-methoxyphenyl)sulfonyl]-1.3-imidazolidine-2-carboxamide,MS(ES): 472 [M+H]⁺;

[0210]N-Hydroxy-1,3-di-[(4-methoxyphenyl)sulfonyl]-hexahydro-pyrimidine-2-carboxamide,MS(ES): 486 [MPH]⁺;

[0211]N-Hydroxy-1,3-di-[(4-methoxyphenyl)sulfonyl]-1,3-diazepine-2-carboxamide,MS(ES): 500 [M+H]⁺;

[0212]N-Hydroxy-1,3-di-[(4-methoxyphenyl)sulfonyl]-5-hydroxy-hexahydro-pyrimidine-2-carboxamide,MS(ES): 502 [M+H]⁺;

[0213]N-Hydroxy-3-[(4-methoxyphenyl)sulfonyl]-2H-tetrahydrooxazine-2(R,S)-carboxamide,MS(ES): 317 [M+H]⁺;−N-Hydroxy-3-[(4-methoxyphenyl)sulfonyl]-2H-1,4-dihydro-3,1-benzooxazine-2-carboxamide,MS(ES): 365 [M−H]⁺.

EXAMPLE 3

[0214] Synthesis of N-hydroxy1-[(4-methoxyphenyl)sulfonyl]-3-[methylsulphonyl]-hexahydro-pyrimidine-2(R,S)-carboxamide (3d).

[0215]1-[(4-Methoxyphenyl)sulfonyl]-3-[t-butyloxy-carbonyl]-1,3-diamino-propane(3a): N-BOC-1,3-diaminopropane (4.5 g, 25.8 mmol) is dissolved in 100 mLdichloromethane and is cooled to 0° C. with an ice bath. To this isadded, carefully, 4-methoxyphenylsulfonyl chloride (5.37 g, 26 mmol)followed by 4-methylmorpholine (7.2 mL, 65 mmol). The reaction isstirred for 45 minutes, warming to room temperature. This mixture isdiluted with 100 mL more of dichloromethane and washed with water. Thesolvents are evaporated and the residue is taken up in 50 mL ethylacetate. Crystals formed upon addition of hexane are collected to give1-[(4-methoxyphenyl)sulfonyl]-3-[t-butyloxy-carbonyl]-1,3-diamino-propane.

[0216] 1-[(4-Methoxyphenyl)sulfonyl-1,3-diamino-propane (3b):1-[(4-Methoxyphenyl)sulfonyl]-3-[t-butyloxy-carbonyl]-1,3-diamino-propane(3 g, 8.7 mmol) is dissolved in 20 mL dichloromethane and to this isadded 7 mL (90.9 mmol) of trifluoroacetic acid. This reaction is stirredfor 3 hours at which time the TLC (100% ethyl acetate) indicates thereaction to be complete. The volatiles are removed aided by azeotropingwith toluene to give 1-[(4-methoxyphenyl)sulfonyl]-1,3-diamino-propanetrifluoroacetate salt as a colorless solid.

[0217]1-[(4-Methoxyphenyl)sulfonyl]-3-[methylsulfonyl]-1,3-diamino-propane(3c): 1-[(4-Methoxyphenyl)sulfonyl]-1.3-diamino-propane trifluoroacetatesalt (500 mg, 1.4 mmol) is dissolved in 15 mL dichloromethane and cooledto 0° C. with an ice bath. To this is added 4-methylmorpholine (0.46 mL,4.2 mmol) followed by methanesulfonyl chloride (0.11 mL, 1.5 mmol). Thereaction is stirred for 30 minutes at which time the TLC (1:1hexane:ethyl acetate) indicated the reaction to be complete. Thereaction is washed with water, dried, and evaporated. The crude productis purified by flash chromatography (7:3 ethyl acetate:hexane) to give1-[(4-methoxyphenyl)sulfonyl]-3-[methylsulfonyl]-1,3-diamino-propane asa colorless solid, MS(ES): 394 [M+H]⁺.

[0218] N-Hydroxy1-[(4-methoxyphenyl)sulfonyl]-3-imethylsulfonyl]-hexahydropyrimidine-2(R,S) carboxamide (3d). Following Example 11-[(4-methoxyphenyl)sulfonyl]-3-[methylsulfonyl]-1,3-diamino-propane isconverted to N-hydroxy1-[(4-methoxyphenyl)sulfonyl]-3-[methylsulfonyl]-hexahydro-pyrimidine-2(R,S)-carboxamide. MS(ES): 448 [M+H]⁺.

EXAMPLE 4

[0219] The following compounds are prepared similarly to Example 3:

[0220]N-hydroxy-1-[(4-methoxyphenyl)sulfonyl]-3-acetyl-hexahydro-pyrimidine-2(R,S)-carboxamide, MS(ES): 358 [M+H]⁺;

[0221]N-hydroxy-1-[(4-methoxyphenyl)sulfonyl]-3-benzoyl-hexahydro-pyrimidine-2(R,S)-carboxamide, MS(ES): 420 [M+H]⁺.

EXAMPLE 5

[0222] Synthesis ofN-hydroxy-1,5-dithia-8,10-diaza-spiro[5.5]undecane-9-carboxamide (5c).

[0223] 1,3-Di-[(4methoxyphenyl)sulfonyl]-2-oxo-propane (5a):1,3-Di-[(4-methoxyphenyl)sulfonyl]-2-hydroxy-propane (1.0 g, 2.3 mmol),prepared from 2-hydroxy-1,3-propanediamine according to Example 1, isdissolved in 20 mL of acetone and the solution is cooled to 0° C. withan ice bath. The Jones reagent is then added until orange colorpersisted and the reaction is allowed to stir overnight at roomtemperature. The reaction is diluted with 100 mL of water and theproduct is extracted into ethyl acetate (3×). The organic extracts arewashed with water (1×) and 10% sodium bicarbonate solution (1×), driedover sodium sulfate, and concentrated under reduced pressure. The crudeproduct is purified by flash silica gel chromatography (6:4 ethylacetate:hexanes) to give1,3-di-[(4-methoxyphenyl)sulfonyl]-2-oxo-propane.

[0224] Methyl 1,5-dithia-8,10-diaza-spiro[5.5]undecane-9-carboxylate(5b): Methyl ester (105 mg, 0.2 mmol), prepared from1,3-di-[(4-methoxyphenyl)sulfonyl]-2-oxo-propane according to Example 1,is dissolved in 20 mL of dichloromethane and to the solution is added1,3-propanedithiol (0.042 mL, 0.4 mmol) followed by boron trifluoridediethyl etherate (0.01 mL, 0.08 mmol). The reaction is stirred for 40hours at room temperature, the pH is adjusted to pH 8 with 1 M aqueoussodium hydroxide and the mixture is washed with ethyl acetate (2×). Thecombined organic phases are washed once with 10% ammonium chloridesolution, dried (Na₂SO₄), and concentrated under reduced pressure. Thecrude product is purified by flash silica gel chromatography (6:4 ethylacetate:hexanes) to give methyl1,5-dithia-8,10-diaza-spiro[5.5]undecane-9-carboxylate.

[0225] N-Hydroxy-1,5dithia-8,10-diaza-spiro[5.5]undecane-9-carboxamide(5c): Methyl 1,5-dithia-8,10-diaza-spiro[5.5]undecane-9-carboxylate isconverted to the target hydroxamic acid similarly to Example 1. MS(ES):590 [M+H]⁺.

EXAMPLE 6

[0226] Synthesis of3-[(4-methoxyphenyl)sulfonyl]-[1,3]thiazinane-2(R,S)-carboxamide (6e).

[0227] 3-[(4-Methoxyphenyl)sulfonyl]-propan-1-ol (6a): The3-aminopropanol (8.0 g, 106.5 mmol), triethylamine (21.6 g. 213 mmol.2.0 equiv) in 1.4-dioxane (75 mL) and water (75 mL) is stirred at roomtemperature and then 4-methoxyphenylsulfonyl chloride (23.1 g, 111.8mmol, 1.05 equiv) is added. The resulting solution is stirred at roomtemperature for 4 h, and then the solution is acidified to pH ˜1 with 1N HCl. The solution is poured into water and then extracted with CH₂Cl₂.The organic extracts are dried (Na₂SO₄) and concentrated to an oil. Theoil is purified by chromatography (1/1 hexane/EtOAc) to give3-[(4-methoxyphenyl)sulfonyl]-propan-1-ol as a colorless oil.

[0228] 1-S-Acetyl-3-[(4-methoxyphenyl)sulfonyl]-propane (6b):3-[(4-Methoxyphenyl)sulfonyl]-propan-1-ol (26.0 g, 106 mmol) in CH₂Cl₂(250 mL) is stirred at room temperature and then methanesulfonylchloride (13.4 g, 117 mmol, 1.1 equiv) and triethylamine (16.0 g, 159mmol, 1.5 equiv) are added. The resulting solution is stirred for onehour at room temperature and then poured into water. The solution isextracted with EtOAc and the organic extracts are dried (Na₂SO₄) andconcentrated to an oil under reduced pressure. The oil is dissolved inDMF (300 mL) and then potassium thioacetate (18 g, 159 mmol, 1.5 equiv)is added. The resulting solution is stirred overnight at roomtemperature and then poured into water. The mixture is extracted withEtOAc, the organic extracts are dried (Na₂SO₄) and then concentrated toan oil under reduced pressure. The resulting oil is purified bychromatography on silica gel (7/3 hexane/EtOAc) to give1-S-acetyl-3-[(4-methoxyphenyl)sulfonyl]-propane as a light yellow oilwhich solidified upon prolonged standing. MS (CI): 304 [M+H]⁺.

[0229] 3-[(4-Methoxyphenyl)sulfonyl]-propane-1-thiol (6c):1-S-acetyl-3-[(4-Methoxyphenyl)sulfonyl]-propane (8.91 g, 29.4 mmol) inmethanol (125 mL) is stirred under an argon atmosphere at roomtemperature. The solution is then bubbled with ammonia gas for 20minutes at room temperature and then the solution is purged with argongas. The solvent is removed under reduced pressure to leave a colorlessoil. Purification of the oil is accomplished by chromatography (8/2hexane/EtOAc) to give 3-[(4-methoxyphenyl)sulfonyl]-propane-1-thiol as acolorless oil. MS (ES): 262 [M−H]⁺.

[0230]Methyl-1-[(4-methoxyphenyl)sulfonyl]-[1,3]thiazinane-2(R,S)-carboxylate(6d): 3-[(4-Methoxyphenyl)suifonyl]-propane-1-thiol (6.90 g, 26.4 mmol)and methyl glyoxylate (158 mL, 79.2 mmol, 3.0 equiv. 0.5 M in Et₂O) isconcentrated to an oil under reduced pressure. The resulting thick oilis then diluted with benzene (100 mL) and 0.1 g p-TsOH is added. Thesolution is heated to reflux and water is removed from the reactionmixture with the aid of a Dean-Stark trap. The solution is cooled toroom temperature and then poured into dilute NaHCO₃ solution (50 mL).The solution is extracted with EtOAc, the organic extracts are dried(Na₂SO₄) and then concentrated to an oil under reduced pressure. Theproduct is purified by chromatography on silica gel (8/2 hexane/EtOAc)to give methyl1-[(4-methoxyphenyl)sulfonyl]-[1,3]thiazinane-2(R,S)carboxylate as acolorless oil which solidified upon standing. MS (CI): 332 [M+H]⁺.

[0231] 1-[(4-Methoxyphenyl)sulfonyl]-[1,3]thiazinane-2(R,S)-carboxamide(6e): Methyl1-[(4-methoxyphenyl)sulfonyl]-[1.3]thiazinane-2(R,S)-carboxylate (0.5 g,1.51 mmol) in methanol (15 mL) is stirred at room temperature and then asolution of KONH₂ (0.868 M in MeOH, 3.5 mL, 3.02 mmol, 2 equiv) isadded. The resulting solution is stirred at room temperature for 24 hand then acidified to pH ˜2 with 1 N HCl. The solution is poured intowater and then extracted with CH₂Cl₂. The organic extracts are dried(Na₂SO₄) and concentrated under reduced pressure to give1-[(4-methoxyphenyl)sulfonyl]-[1,3]thiazinane-2(R,S)-carboxamide as awhite solid. MS (ES): 333 [M+H]⁺.

EXAMPLE 7

[0232] Synthesis ofN-hydroxy-3-[(4-methoxyphenyl)sulfonyl]-2,5,5′-trimethyl-thiazolidine-2(R,S)-carboxamide(7d).

[0233] Ethyl 2,5,5′-trimethyl-thiazolidine-2(R,S)-carboxylate (7a):1-Amino-2-methyl-2-propanethiol (25.11 g, 177 mmol) and ethyl pyruvate(20.58 g, 177 mmol) are suspended in benzene (300 mL) and heated toreflux in a flask equipped with a Dean-Stark trap. Two drops of sulfuricacid are added. The reaction is allowed to stir further at reflux for 3hours. The volatiles are removed to give ethyl2,5,5′-trimethyl-thiazolidine-2(RS)-carboxylate as a white solid.

[0234] Ethyl3-[(4-methoxyphenyl)sulfonyl]-2,5,5′-trimethyl-thiazolidine-2(R,S)-carboxylate(7b): Ethyl 2.5,5′-trimethyl-thiazolidine-2(R,S)-carboxylate (40.39 g,168 mmol) and 4-methoxyphenylsulfonyl chloride (35.13 g, 170 mmol) ofare dissolved in pyridine (138 mL) and heated at reflux for 1 hour.After cooling to room temperature the solution is diluted with 1Maqueous hydrochloric acid and the product is extracted into diethylether (3×). The combined organic phases are dried (Na₂SO₄) andconcentrated under reduced pressure to give ethyl3-[(4-methoxyphenyl)sulfonyl]-2,5,5′-trimethyl-thiazolidine-2(R,S)-carboxylateas a red oil.

[0235]N-t-Butyloxy-3-[(4-methoxyphenyl)sulfonyl]-2,5,5′-trimethyl-thiazolidine-2(R,S)-carboxamide(7c): Ethyl3-[(4-methoxyphenyl)sulfonyl]-2,5,5′-trimethyl-thiazolidine-2(R,S)-carboxylate(53.26 g, 143 mmol) is dissolved in 1M aqueous sodium hydroxide (285 mL)and ethanol (500 mL) and is heated to reflux for 5 hours. The reactionis cooled to room temperature and the mixture is stirred further for 16hours. The reaction is then neutralized with 1M aqueous hydrochloricacid and the volatiles are removed under reduced pressure to give3-[(4-methoxyphenyl)sulfonyl]-2,5,5′-trimethyl-thiazolidine-2(R,S)-carboxylicacid. The acid is dissolved in N,N-dimethylformamide (500 mL) and thesolution is cooled to 0° C. with an ice bath. To this is added1-hydroxybenzotriazole (38.3 g, 284 mmol), 4-methylmorpholine (46.7 mL,425 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (40.8 g, 213mmol) followed, after 30 minutes, with O-tert-butylhydroxylaminehydrochloride (18 g, 143 mmol). The reaction is stirred for 16 hours atroom temperature, water (750 mL) is added and the product is extractedwith ethyl acetate (2×). The combined organic phases are washed with 10%sodium bicarbonate (2×), dried (Na₂SO₄) and concentrated under reducedpressure to giveN-t-butyloxy-3-[(4-methoxyphenyl)sulfonyl]-2,5,5′-trimethyl-thiazolidine-2(R,S)-carboxamideas an oil.

[0236]N-Hydroxy-3-[(4-methoxyphenyl)sulfonyl]-2,5,5′-trimethyl-thiazolidine-2(R,S)-carboxamide(7d):N-t-Butyloxy-3-[(4-methoxyphenyl)sulfonyl]-2,5,5′-trimethyl-thiazolidine-2(R,S)-carboxamide(49.0 g, 118 mmol) is dissolved in dichloroethane (700 mL) and ethanol(50 mL) and the solution is cooled to 0 C. Hydrochloride gas is bubbledthrough the solution for 20 minutes. The reaction is then sealed and isstirred for 16 hours. Hydrochloride gas is again bubbled through thereaction for 1 hour. The reaction is sealed and is stirred for 72 hours.The volatiles are removed under reduced pressure to give a dark, thickoil. The crude product is purified by silica gel flash chromatography togiveN-hydroxy-3-[(4-methoxyphenyl)sulfonyl]-2,5,5′-trimethyl-thiazolidine-2(R,S)-carboxamideas a white solid. MS (ES): 361 [M+H]⁺.

EXAMPLE 8

[0237] The following compounds are prepared similarly to Example 7:

[0238]N-Hydroxy-3-[(4-methoxyphenyl)sulfonyl]-5,5-dimethyl-thiazolidine-2(R,S)-carboxamide,MS (ES) 347 [M+H]⁺;

[0239]N-Hydroxy-[(4-methoxyphenyl)sulfonyl)-thiazolidine-2(R,S)-carboxamide,MS (ES) 319 [M+H]⁺.

EXAMPLE 9

[0240] Synthesis ofN-hydroxy-1-[(4-methoxyphenyl)sulfonyl]-3-phenylmethyl-4-oxo-5,5dimethyl-hexahydro-pyrimidine-2-carboxamide(9d).

[0241] 3-[(4-Methoxyphenyl)sulfonyl]-2,2-dimethyl-propanol (9a):3-Amino-2,2-dimethylpropanol (5.16 g, 50 mmol) is dissolved in 1:1dioxane-water (500 mL), cooled to 0° C. followed by addition oftriethylamine (17.4 mL, 125 mmol), and 4-methoxybenzene sulfonylchloride (10 g, 48.39 mmol). The reaction is stirred for 1 hour, water(250 mL) is added and the mixture is extracted with ethyl acetate (2×).The combined organic phases are washed with brine, dried (Na₂SO₄) andconcentrated under reduced pressure to give3-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-propanol as a white solid.

[0242] 3-[(4-Methoxyphenyl)sulfonyl]-2,2-dimethyl-3-aminopropionic acid(9b): 3-[(4 Methoxyphenyl)sulfonyl]-2,2-dimethyl-propariol (5 g, 18.3mmol) is dissolved in acetone (150 mL). The Jones reagent is then addeduntil orange color persisted and the reaction is allowed to stirovernight at room temperature. The reaction is diluted with 300 mL ofwater and the product is extracted into ethyl acetate (3×). The organicextracts are washed with water (1×) and 10% sodium bicarbonate solution(1×). dried over sodium sulfate, and concentrated under reduced pressureto give

[0243] 3-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-3-aminopropionic acid.3-[(4-Methoxyphenyl)sulfonyl]-2,2-dimethyl-3-aminopropionic acidphenylmethyl amide (9c):3-[(4-Methoxyphenyl)sulfonyl]-2,2-dimethyl-3-aminopropionic acid (863mg, 3 mmol), 1-hydroxybenzotriazole (1.37 g, 9 mmol) and4-methylmorpholine (1 mL, 9 mmol) are dissolved in N,N-dimethylformamide (10 mL), the solution is cooled to 0° C. andl-ethyl-3-(3-dimethylaminopropyl)carbodiimide (690 m, 3.6 mmol). Thesolution is stirred for 30 minutes, benzylamine (322 mg, 3 mmol) isadded and the solution is stirred for 2 hours at room temperature. Water(10 mL) is added and the product is extracted with ethyl acetate (2×).The combined organic phases are washed with 10% sodium bicarbonate andbrine, dried (Na₂SO₄) and concentrated under reduced pressure to give3-[(4-methoxyphenyl)sulfonyl]-2,2-dimethyl-3-aminopropionic acidphenylmethyl amide.

[0244]N-Hydroxy-1-[(4-methoxyphenyl)sulfonyl]-3-phenylmethyl-4-oxo-5,5dimethyl-hexahydropyrimidine-2-carboxamide(9d): 3-[(4-Methoxyphenyl)sulfonyl]-2,2-dimethyl-3-aminopropionic acidphenylmethyl amide is converted to the target hydroxamic acid similarlyto Example 1. MS(ES): 448 [M+H]⁺.

EXAMPLE 10

[0245] The following compounds are prepared similarly to Example 9:

[0246]N-Hydroxy-1-[(4-methoxyphenyl)sulfonyl]-3-methyl-4-oxo-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide,MS (ES) 372 [M+H]⁺;

[0247]N-Hydroxy-1-[(4-methoxyphenyl)sulfonyl]-3-(2-phenylethyl)-4-oxo-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide,MS (ES) 462 [M+H]⁺;

[0248]N-Hydroxy-1-t(4-methoxyphenyl)sulfonyl]-3-isopropyl-4-oxo-5,5-dinethyl-hexahydro-pyrimidine-2-carboxamide,MS (ES) 400 [M+H]⁺;

[0249]N-Hydroxy-1-[(4-buthoxyphenyl)sulfonyl]-3-isopropyl-4-oxo-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide,MS (ES) 442 [M+H]⁺;

[0250]N-Hydroxy-1-[(4-buthoxyphenyl)sulfonyl]-3-phenyl-4-oxo-5,5-dimethyl-hexahydro-pyrimidine-2-carboxamide,MS (ES) 476 [M+H]⁺;

[0251]N-Hydroxy-1-(4-buthoxyphenyl)sulfonyt]-3-(2-thienylmethyl)-4-oxo-5.5-dimethyl-hexahydro-pyrimidine-2-carboxamide,MS (ES) 496 [M+H]⁺;

[0252]N-Hydroxy-1-[(4-methoxyphenyl)sulfonyl]-3-methyl-4-oxo-diazolidine-2-carboxamide,MS (ES) 330 [M+H]⁺;

EXAMPLE 11

[0253] Synthesis of N-hydroxy2,4-dioxo-3-methyl-9-[(4-methoxyphenyl)sulfonyl]-1,3,9-triaza[3.5.0]^(1,5)bicyclodecane-10-carboxamide(11c).

[0254] 2S-Amino-5-[(4-methoxyphenyl)sulfonylamino]-caproic acid methylamide (11a). N-(tert-Butoxycarbonyl)-L-ornithine (4.5 g. 19.4 mmol) isdissolved in 1:1 v/v 1,4-dioxane and water (200 mL). The mixture iscooled to 0° C. with an ice bath, triethylamine (3.6 mL, 28 mmol) isadded followed by 4-methoxybenzenesulfonyl chloride (4.2 g, 20 mmol).The ice bath is removed and the solution is allowed to stir for onehour. The solution is then acidified to pH 5 with 1 M aqueoushydrochloric acid and the product is extracted into ethyl acetate (500mL ). The ethyl acetate mixture is washed with water (2×150 mL). Theorganic phase is dried over sodium sulfate and concentrated underreduced pressure to give the desired sulfonamide as a white solid. MS(ESI) 403 (M+H)⁺.

[0255] The sulfonamide is dissolved in N,N-dimethylformamide (250 mL)and this solution is cooled to 0° C. To this is added1-hydroxybenzotriazole (2.84 g, 21 mmol), 4-methylmorpholine (3.1 mL, 28mmol), and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (1.59 g, 8.3mmol). The reaction is stirred 10 minutes and then methylaminehydrochloride (500 mg, 7.4 mmol) is added. The ice bath is removed andthe mixture is stirred at ambient temperature for 16 hours. Water (200mL) is then added and the product is extracted into ethyl acetate (500mL). The ethyl acetate solution is washed with water (3×150 mL each).The ethyl acetate mixture is then dried over sodium sulfate andconcentrated under reduced pressure to give the desired methylamide as awhite solid. MS (ESI) 416 (M+H)⁺.

[0256] The amide (2.247 g 5.4 mmol) is dissolved in dichloromethane (25mL) and to this is added trifluoroacetic acid (1.7 mL, 22 mmol). Thereaction is stirred for four hours and then the volatiles are removedunder reduced pressure to give an oil. The crude product is driedfurther on a vacuum pump for 16 hours to give2S-amino-5-[(4-methoxyphenyl)sulfonylamino]-caproic acid methyl amide.MS (ESI) 316 (M+H)⁺.

[0257] 3-Methyl-5S-[3-[(4-methoxyphenyl)sulfonylamino]propyl]-hydantoine(11b). 2S-Amino-5-[(4-methoxyphenyl)sulfonylamino]-caproic acid methylamide (1.7 g, 5.4 mmol) is dissolved in dichloromethane (150 mL) andcooled to −20° C. To this is added N,N-diisopropylethylamine (2.5 mL, 14mmol) followed by triphosgene (964 mg, 3.3 mmol). The −20° C. bath isreplaced with an ice bath and the reaction is stirred for 45 minutes.The mixture is poured on ice and the product is extracted with ethylacetate. The ethyl acetate solution is washed with water and brine, thendried over sodium sulfate and concentrated under reduced pressure. Thecrude product is purified by silica gel flash chromatography to give3-methyl-5S-[3-[(4-methoxyphenyl)sulfonylamino]propyl]-hydantoine. MS(ESI) 342 (M+H)⁺.

[0258] N-Hydroxy2,4-dioxo-3-methyl-9-[(4-methoxyphenyl)sulfonyl]-1,3,9-triaza[3.5.0]bicyclodecane-10-carboxamide(11c). 3-Methyl-5S-[3-[(4-methoxyphenyl)sulfonylamino]propyl]-hydantoine(200 ma, 0.6 mmol) is dissolved in benzene (75 mL) in a round bottomflask equipped with a Dean-Stark trap. To this is added methylglyoxylate (287 mg, 3.68 mmol) followed by a catalytic amount ofsulfuric acid. The mixture is refluxed for 30 minutes with removal ofwater by the Dean-Stark trap. The reaction is allowed to cool to ambienttemperature and the reaction mixture is diluted with ethyl acetate (100mL). The ethyl acetate mixture is washed once with water (25 mL) andthen is dried over sodium sulfate and is evaporated under reducedpressure to give the crude desired methyl ester. MS (ESI) 411 (M+H)⁺.

[0259] The methyl ester (220 mg, 0.53 mmol) is treated with 2.1 mL ofNH₂OK (1.76 M in methanol, solution prepared as described in Fieser andFieser, Vol. 1, p. 478). The reaction stirs 3 hours at room temperature.The reaction is neutralized with 1M aqueous HCl and the diastereomersare extracted into ethyl acetate. The organics are dried over sodiumsulfate and the volatiles are removed under reduced pressure. The crudeproduct is purified by high pressure liquid chromatography to giveN-hydroxy2,4-dioxo-3-methyl-9-[(4-methoxyphenyl)sulfonyl]-1,3,9-triaza[3.5.0]^(1,5)bicyclodecane-10-carboxamideas a colorless solid. MS (ESI) 413 (M+H)⁺, 430 (M+NH₄)⁺, 435 (M+Na)⁺.

EXAMPLES 12-65

[0260] The following compounds are made using the methods described andexemplified above.

X Y Z Ar n Example 12 C₆H₅CH₂ CO — 4-(C₆H₅O)—C₆H₄— 2 Example 13 C₆H₅CH₂CO — 4-Br—C₆H₄— 2 Example 14 C₆H₅CH₂ CO — 4-n-BuO—C₆H₄— 2 Example 15C₆H₅CH₂ CO — 4-NO₂—C₆H₄— 2 Example 16 C₆H₅CH₂ CO 4,4-(CH₃)₂ 4-NO₂—C₆H₄—1 Example 17 C₆H₅CH₂ CO 4,4-(CH₃)₂ 4-n-BuO—C₆H₄— 1 Example 18 C₆H₅CH₂ CO4,4-(CH₃)₂ 4-i-BuO—C₆H₄— 1 Example 19 C₆H₅CH₂ CO 4,4-(CH₃)₂4-(C₆H₅O)—C₆H₄— 1 Example 20 C₆H₅CH₂ CO 4,4-(CH₃)₂ 4-(4-F—C₆H₄O)—C₆H₄— 1Example 21 C₆H₅CH₂ CO 4,4-(CH₃)₂ 4-(4-Cl—C₆H₄O)—C₆H₄— 1 Example 22C₆H₅CH₂ CO 4,4-(CH₃)₂ 4-(4-Br—C₆H₄O)—C₆H₄— 1 Example 23 C₆H₅CH₂ CO4,4-(CH₃)₂ 4-(4-Me-C₆H₄O)—C₆H₄— 1 Example 24 C₆H₅CH₂ CO 4,4-(CH₃)₂4-(4-MeO—C₆H₄O)—C₆H₄— 1 Example 25 C₆H₅CH₂ CO 4,4-(CH₃)₂4-(4-CN—C₆H₄O)—C₆H₄— 1 Example 26 C₆H₅CH₂ CO 4,4-(CH₃)₂4-(4-Me₂N—C₆H₄O)—C₆H₄— 1 Example 27 4-EtO—C₆H₄SO₂— — 4,4-(CH₃)₂4-EtO—C₆H₄— 1 Example 28 4-i-PrO—C₆H₄SO₂— — 4,4-(CH₃)₂ 4-i-PrO—C₆H₄— 1Example 29 4-n-PrO—C₆H₄SO₂— — 4,4-(CH₃)₂ 4-n-PrO—C₆H₄— 1 Example 304-Br—C₆H₄SO₂— — 4,4-(CH₃)₂ 4-Br—C₆H₄— 1 Example 31 2-CH₃-4-Br—C₆H₃SO₂— —4,4-(CH₃)₂ 2-CH₃-4-Br—C₆H₃— 1 Example 32 C₆H₅ CO 4,4-(CH₃)₂ 4-C₆H₅—C₆H₄—1 Example 33 C₆H₅ CO 4,4-(CH₃)₂ 4-(4-F—C₆H₅)—C₆H₄— 1 Example 34 C₆H₅ CO4,4-(CH₃)₂ 4-(4-Cl—C₆H₅)—C₆H₄— 1 Example 35 C₆H₅ CO 4,4-(CH₃)₂4-(4-Br—C₆H₅)—C₆H₄— 1 Example 36 C₆H₅ CO 4,4-(CH₃)₂4-(4-Me₂N—C₆H₄)—C₆H₄— 1 Example 37 C₆H₅ CO 4,4-(CH₃)₂4-(4-CN—C₆H₄)—C₆H₄— 1 Example 38 C₆H₅ CO 4,4-(CH₃)₂ 4-(4-MeO—C₆H₄)—C₆H₄—1 Example 39 C₆H₅ CO 4,4-(CH₃)₂ 4-(4-C₅H₄NO)—C₆H₄— 1 Example 40 C₆H₅ CO4,4-(CH₃)₂ 4-(3-C₅H₄NO)—C₆H₄— 1 Example 41 C₆H₅ CO 4,4-(CH₃)₂4-(2-C₅H₄NO)—C₆H₄— 1 Example 42 C₆H₅ CO 4,4-(CH₃)₂ C₆H₅CH₂CH₂— 1 Example43 C₆H₅ CO — C₆H₅CH₂— 2 Example 44 C₆H₅CH₂ CO — (4-C₅H₄N)CH₂CH₂— 2Example 45 C₆H₅CH₂ CO — (2-C₅H₄N)CH₂CH₂— 2 Example 46 C₆H₅CH₂ CO —4-(C₆H₁₁O)—C₆H₄— 2 Example 47 C₆H₅CH₂ CO — 4-(C₅H₁₁O)—C₆H₄— 2 Example 48C₆H₅CH₂ CO — 4-(C₆H₁₃O)—C₆H₄— 2 Example 49 C₆H₅CH₂ CO —4-(CH₃OCH₂CH₂O)—C₆H₄— 2 Example 50 (CH₃)₂CH CO — 4-PhOC₆H₄— 0 Example 51(CH₃)₂CH CO — 4-FC₆H₄OC₆H₄— 0 Example 52 (CH₃)₂CH CO — 4-EtOC₆H₄— 0Example 53 (CH₃)₂CH CO — 4-(CH₃)₂CHOC₆H₄— 0 Example 54 (CH₃)₂CH CO —4-nPrOC₆H₄— 1 Example 55 4-MeOC₆H₄SO₂— — 4(-OCH₂CH₂O—) 4-MeOC₆H₄— 1Example 56 4-MeOC₆H₄SO₂— — 4(-SCH₂CH₂S—) 4-MeOC₆H₄— 1 Example 574-MeOC₆H₄SO₂— — 4(-OCH₂CH₂CH₂O—) 4-MeOC₆H₄— 1 Example 58 4-MeOC₆H₄SO₂— —4,4-(OMe)₂ 4-MeOC₆H₄— 1 Example 59 C₆H₅CH₂CH₂— CO 4,4-(CH₃)₂5-(2-pyridinyl)-2-thienyl- 1 Example 60 C₆H₅CH₂CH₂— CO 4,4-(CH₃)₂5-(3-isoxazolyl)-2-thienyl- 1 Example 61 C₆H₅CH₂CH₂— CO 4,4-(CH₃)₂5-(2-(methylthio)pyrimidin- 1 4-yl)-2-thienyl- Example 62 C₆H₅CH₂CH₂— CO4,4-(CH₃)₂ 5-(3-(1-methyl-5- 1 (trifluoromethyl)pyrazolyl)- 2-thienyl-Example 63 nBu- CO 4,4-(CH₃)₂ 5-(2-pyridinyl)-2-thienyl- 1 Example 644-nBuOC₆H₄SO₂— H 4(-OCH₂CH₂O—) 4-nBuOC₆H₄— 1 Example 65 4-nBuOC₆H₄SO₂— H4(OEt)₂ 4-nBuOC₆H₄— 1

[0261] Methods:

[0262] Examples 12-65 are prepared analogously to Example 1,3,5 and 9using the appropriately functionalized sulfonyl chloride. The sulfonylchlorides which are used to prepare the above examples are eitherpurchased from commericial sources or prepared via known methods. Forexample, the 4-phenoxyphenylsulfonyl chloride used for the preparationof Example 12, was prepared as described by R. J. Cremlyn et al in Aust.J. Chem., 1979, 32, 445.52.

[0263] These examples provide the skilled artisan with sufficientguidance as to making the present invention and do not limit it in anyway.

[0264] Composition and Method of Use Examples

[0265] The compounds of the invention are useful to prepare compositionsfor the treatment of ailments and the like. The following compositionand method examples do not limit the invention, but provide guidance tothe skilled artisan to prepare and use the compounds, compositions andmethods of the invention. In each case the compounds formula I may besubstituted for the example compound shown below with similar results.

[0266] The methods of use exemplified do not limit the invention, butprovide guidance to the skilled artisan to use the compounds,compositions and methods of the invention. The skilled practitioner willappreciate that the examples provide guidance and may be varied based oncondition and the patient.

Example A

[0267] A tablet composition for oral administration, according to thepresent invention, is made comprising: Component Amount Example 9 15. mgLactose 120. mg  Maize Starch 70. mg Talc  4. mg Magnesium Stearate  1.mg

[0268] Other compounds having a structure according to Formula (I) areused with substantially similar results.

[0269] A human female subject weighing 60 kg (132 lbs), suffering fromrheumatoid arthritis, is treated by a method of this invention.Specifically, for 2 years, a regimen of three tablets per day isadministered orally to said subject.

[0270] At the end of the treatment period, the patient is examined andis found to have reduced inflammation, and improved mobility withoutconcomitant pain.

Example B

[0271] A capsule for oral administration, according to the presentinvention, is made comprising: Component Amount (% w/w) Example 3 15%Polyethylene glycol 85%

[0272] Other compounds having a structure according to Formula (I) areused with substantially similar results.

[0273] A human male subject weighing 90 kg (198 lbs), suffering fromosteoarthritis, is treated by a method of this invention. Specifically,for 5 years, a capsule containing 70 mg of Example 3 is administereddaily to said subject.

[0274] At the end of the treatment period, the patient is examined viaorthoscopy, and found to have no further advancement oferosion/fibrillation of the articular cartilage.

Example C

[0275] A saline-based composition for local administration, according tothe present invention, is made comprising: Component Amount (% w/w)Example 13  5% Polyvinyl alcohol 15% Saline 80%

[0276] Other compounds having a structure according to Formula (I) areused with substantially similar results.

[0277] A patient having deep corneal abrasion applies the drop to eacheye twice a day. Healing is speeded, with no visual sequelae.

Example D

[0278] An topical composition for local administration, according to thepresent invention, is made comprising: Component Composition (% w/v)Compound of Example 3 0.20 Benzalkonium chloride 0.02 Thimerosal 0.002d-Sorbitol 5.00 Glycine 0.35 Aromatics 0.075 Purified water q.s. Total =100.00 Total = 100.00

[0279] Any of the other compounds having a structure according toFormula (1) are used with substantially similar results.

[0280] A patient suffering from chemical burns applies the compositionat each dressing change (b.i.d.). Scarring is substantially diminished.

Example E

[0281] A inhalation aerosol composition, according to the presentinvention, is made comprising: Component Composition (% w/v) Compound ofExample 2 5.0 Alcohol 33.0 Ascorbic acid 0.1 Menthol 0.1 SodiumSaccharin 0.2 Propellant (F12, F114) q.s. Total = 100.0

[0282] Any of the other compounds having a structure according toFormula (1) are used with substantially similar results.

[0283] An asthma sufferer sprays 0.01 mL via a pump actuator into themouth while inhaling. Asthma symptoms are diminished.

Example F

[0284] A topical opthalmic composition, according to the presentinvention, is made comprising: Component Composition (% w/v) Compound ofExample 5 0.10 Benzalkonium chloride 0.01 EDTA 0.05Hydroxyethylcellulose (NATROSOL M ™) 0.50 Sodium metabisulfite 0.10Sodium chloride (0.9%) q.s. Total = 100.0

[0285] Any of the other compounds having a structure according toFormula (I) are used with substantially similar results.

[0286] A human male subject weighing 90 kg (198 lbs), suffering fromcorneal ulcerations, is treated by a method of this invention.Specifically, for 2 months, a saline solution containing 10 mg ofExample 5 is administered to said subject's affected eye twice-daily.

Example G

[0287] A composition for parenteral administration is made comprising:Amount Component Example 4 100 mg/ml carrier Carrier: sodium citratebuffer with (percent by weight of carrier): lecithin 0.48%carboxymethylcellulose 0.53 povidone 0.50 methyl paraben 0.11 propylparaben 0.011

[0288] The above ingredients are mixed, forming a suspension.Approximately 2.0 ml of the suspension is administered, via injection,to a human subject with a premetastatic tumor. The injection sitejuxtaposes the tumor. This dosage is repeated twice daily, forapproximately 30 days. After 30 days, symptoms of the disease subside,and dosage is gradually decreased to maintain the patient.

[0289] Other compounds having a structure according to Formula I areused with substantially similar results.

Example H

[0290] A mouthwash composition is prepared; Component % w/v Example 13.00 SDA 40 Alcohol 8.00 Flavor 0.08 Emulsifier 0.08 Sodium Fluoride0.05 Glycerin 10.00 Sweetener 0.02 Benzole acid 0.05 Sodium hydroxide0.20 Dye 0.04 Water balance to 100%

[0291] A patient with gum disease uses 1 ml of the mouthwash thricedaily to prevent further oral degeneration.

[0292] Other compounds having a structure according to Formula I areused with substantially similar results.

Example I

[0293] A lozenge composition is prepared; Component % w/v Example 3 0.01Sorbitol 17.50 Mannitol 17.50 Starch 13.60 Sweetener 1.20 Flavor 11.70Color 0.10 Corn Syrup balance to 100%

[0294] A patient uses the losenge to prevent loosening of an implant inthe maxilla. Other compounds having a structure according to Formula Iare used with substantially similar results.

Example J Chewing Gum Composition

[0295] Component w/v % Example 1 0.03 Sorbitol crystals 38.44 Paloja-Tgum base* 20.00 Sorbitol (70% aqueous solution) 22.00 Mannitol 10.00Glycerine 7.56 Flavor 1.00

[0296] A patient chews the gum to prevent loosening to prevent looseningof dentures.

[0297] Other compounds having a structure according to Formula I areused with substantially similar results.

Example K

[0298] Components w/v % USP Water 54.656 Methylparaben 0.05Propylparaben 0.01 Xanthan Gum 0.12 Guar Gum 0.09 Calcium carbonate12.38 Antifoam 1.27 Sucrose 15.0 Sorbitol 11.0 Glycerin 5.0 BenzylAlcohol 0.2 Citric Acid 0.15 Coolant 0.00888 Flavor 0.0645 Colorant0.0014

[0299] Example 1 is prepared by first mixing 80 kg of gylcerin and allof the benzyl alcohol and heating to 65 C, then slowly adding and mixingtogether methylparaben, propylparaben, water, xanthan gum, and guar gum.Mix these ingredients for about 12 minutes with a Silverson in-linemixer. Then slowly add in the following ingredients in the followingorder: remaining glycerin, sorbitol antifoam C, calcium carbonate,citric acid, and sucrose. Separately combine flavors and coolants andthen slowly add to the other ingredients. Mix for about 40 minutes.

[0300] The patient takes the formulation to prevent flare up of colitis.

[0301] All references described herein are hereby incorporated byreference.

[0302] While particular embodiments of the subject invention have beendescribed, it will be obvious to those skilled in the art that variouschanges and modifications of the subject invention can be made withoutdeparting from the spirit and scope of the invention. It is intended tocover, in the appended claims, all such modifications that are withinthe scope of this invention.

What is claimed is:
 1. A compound having a structure according toFormula (1)

wherein R₁ is H; R₂ is hydrogen, alkyl, or acyl; Ar is COR₃ or SO₂R₄;and R₃ is alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl,heteroalkyl, amino, alkylamino, dialkylamino, arylamino andalkylarylamino; R₄ is alkyl, heteroalkyl aryl, or heteroaryl,substituted or unsubstituted; X is O, S, SO, SO₂, or NR₅, wherein R₅ isindependently chosen from hydrogen, alkyl, heteroalkyl, heteroaryl,aryl, SO₂R₆, COR₇, CSR₈, PO(R₉)₂ or may optionally form a ring with Y orW; and R₆ is alkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino,dialkylamino, arylamino, diarylamino and alkylarylamino; R₇ is hydrogen,alkoxy, aryloxy, heteroaryloxy, alkyl, aryl, heteroaryl, heteroalkyl,amino, alkylamino, dialkylamino, arylamino and alkylarylamino; R₈ isalkyl, aryl, heteroaryl, heteroalkyl, amino, alkylamino, dialkylamino,arylamino, diarylamino and alkylarylamino; R₉ is alkyl, aryl,heteroaryl, heteroalkyl; W is hydrogen or one or more lower alkylmoieties, or a heterocycle, or is an alkylene, arylene or heteroarylenebridge between two adjacent or nonadjacent carbons (thus forming a fusedring); Y is independently one or more of hydrogen, hydroxy, SR₁₀, SOR₄,SO₂R₄, alkoxy, amino, wherein amino is of formula NR₁₁,R₁₂, wherein R₁₁and R₁₂ are independently chosen from hydrogen, alkyl, heteroalkyl,heteroaryl, aryl, SO₂R₆, COR₇, CSR₉, PO(R₉)₂; and R₁₀ is hydrogen,alkyl, aryl, heteroaryl; Z is nil, a spiro moiety or an oxo groupsubstituted on the heterocyclic ring; n is 1-4. This structure alsoincludes an optical isomer, diastereomer or enantiomer for Formula (I),or a pharmaceutically-acceptable salt, or biohydrolyzable amide, esteror imide thereof.
 2. The compound of claim 1, wherein X is O, S, SO,SO₂, or NR₅, wherein R₅ is independently chosen from hydrogen, alkyl,heteroalkyl, heteroaryl, aryl, SO₂R₇, CORG, CSR₉.
 3. The compound ofclaim 1, wherein Ar is SO₂R₄ and R₄ is alkyl, heteroalkyl, aryl, orheteroaryl, substituted or unsubstituted.
 4. The compound of claim 1,wherein Ar is phenyl or substituted phenyl.
 5. The compound of claim 4,wherein Ar is substituted phenyl and the substitution is with hydroxy,alkoxy, nitro or halo.
 6. The compound of claim 5, wherein Ar issubstituted with methoxy, bromo, nitro and butoxy.
 7. The compound ofclaim 6, wherein Ar is substituted at the ortho or para positionrelative to the sulfonyl.
 8. The compound of claim 1, wherein W is oneor more of hydrogen or C₁ to C₄ alkyl.
 9. The compound of claim 1,wherein W is geminal C₁ to C₄ alkyl.
 10. The compound of claim 1,wherein Z is an oxo moiety substituted on the heterocyclic ring.
 11. Thecompound of claim 1, wherein Z is a spiro moiety substituted on theheterocyclic ring.
 12. A pharmaceutical composition comprising: (a) asafe and effective amount of a compound of claim 1; and (b) apharmaceutically-acceptable carrier.
 13. A pharmaceutical compositioncomprising: (a) a safe and effective amount of a compound of claim 4;and (b) a pharmaceutically-acceptable carrier.
 14. A pharmaceuticalcomposition comprising: (a) a safe and effective amount of a compound ofclaim 5; and (b) a pharmaceutically-acceptable carrier.
 15. Apharmaceutical composition comprising: (a) a safe and effective amountof a compound of claim 9; and (b) a pharmaceutically-acceptable carrier.16. A pharmaceutical composition comprising: (a) a safe and effectiveamount of a compound of claim 10; and (b) a pharmaceutically-acceptablecarrier.
 17. A method for preventing or treating a disease associatedwith unwanted as metalloprotease activity in a mammalian subject, themethod comprising administering to said subject a safe and effectiveamount of a compound of claim
 1. 18. A method for preventing or treatinga disease associated with unwanted metalloprotease activity in amammalian subject, the method comprising administering to said subject asafe and effective amount of a compound of claim
 4. 19. A method forpreventing or treating a disease associated with unwantedmetalloprotease activity in a human or other animal subject, the methodcomprising administering to said subject a safe and effective amount ofa compound of claim
 5. 20. A method for preventing or treating a diseaseassociated with unwanted metalloprotease activity in a mammaliansubject, the method comprising administering to said subject a safe andeffective amount of a compound of claim
 9. 21. A method for preventingor treating a disorder modulated by metalloproteases, wherein thedisorder is chosen from the group comprising, arthritis, cancer,cardiovascular disorders, skin disorders, ocular disorders, inflammationand gum disease by administering to a mammal in need of such treatment,a safe and effective amount of a metalloprotease inhibitor according toclaim
 1. 22. A method for preventing or treating a disorder according toclaim 21, wherein the disorder is arthritis, and is chosen from thegroup comprising, osteoarthritis and rheumatoid arthritis.
 23. A methodfor preventing or treating a disorder according to claim 21, wherein thedisorder is cancer, and the treatment prevents or arrests tumor growthand metastasis.
 24. A method for the preventing or treating a disorderaccording to claim 21, wherein the disorder is a cardiovascular disorderchosen from the group compromising dilated cardiomyopathy, congestiveheart failure, atherosclerosis, plaque rupture, reperfusion injury,ischemia chronic obstructive pulmonary disease, angioplasty restenosisand aortic aneurysm.
 25. A method for the preventing or treating adisorder according to claim 21, wherein the disorder is an oculardisorder, and is chosen from the group comprising, corneal ulceration,lack of corneal healing, macular degeneration, and pterygium.
 26. Amethod for preventing or treating a disorder according to claim 21,wherein the disorder is gum disease, and is chosen from the groupcomprising, periodontal disease, and gingivitis.
 27. A method forpreventing or treating a condition, according to claim 21, wherein thecondition is skin condition chosen from the group comprising wrinklerepair and prevention, U, V, skin damage, epidermolysis bullosa,psoriasis, sclerodema, atopic dermatitis and scarring.
 28. A method forpreventing the loosening of prosthetic devices chosen from the groupcomprising joint replacements and dental prosthesis by administering toa mammal in need of such treatment, a safe and effective amount of ametalloprotease inhibitor according to claim
 1. 29. A method fortreating inflammatory conditions according to claim 21, chosen from thegroup comprising inflammatory bowel disease, Crohn's Disease, ulcerativecolitis, pancreatitis, diverticulitis, acne inflammation, osteomylitis,bronchitis, arthritis, asthma.
 30. A method of treating multiplesclerosis, comprising administering to a mammal in need of suchtreatment, a safe and effective amount of a metalloprotease inhibitoraccording to claim
 1. 31. A method for treating musculoskeletal diseaseor cachexia comprising administering to a mammal in need of suchtreatment, a safe and effective amount of a metalloprotease inhibitoraccording to claim 1.